Pharmaceutical materials and methods for their preparation and use

ABSTRACT

Pharmaceutical compositions comprising crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the active pharmaceutical ingredients to a patient. The crystals are typically combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing predetermined amounts of the pharmaceuticals. Also provided are methods for preparing the crystals, and methods for storing and administering the active pharmaceutical ingredient either included within the crystals or upon reconstitution of the crystals to a solution.

This Application claims the benefit of Provisional Application No. 60/138,912 filed on Jun. 11, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical formulations involving the inclusion of an active pharmaceutical ingredient (“API”) in a pharmaceutically-acceptable single crystal matrix. More particularly, the crystals contain growth-sector specific, oriented inclusions of active pharmaceutical ingredients which are isolated. The active pharmaceutical ingredients have higher stability and shelf-life, and can be delivered in conventional dosage forms. This invention has general application to active pharmaceutical ingredients, and in one aspect has particular application to biopharmaceuticals. As used herein, the term “biopharmaceuticals” is used to refer to a subset of API's which are polymeric in nature, including for example, proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids.

2. Description of the Prior Art

There is a continuing need for pharmaceutical compositions which are capable of maintaining the quality and efficacy of the API during storage and delivery. The loss of potency of an API is a critical concern in assuring that viable, effective drugs are delivered to patients. It is similarly desirable to have formulations which do not require special package or handling. Further, it remains a constant goal to provide active pharmaceutical ingredients in a form which facilitates their use by the consumer, such as though convenient dosage forms. The present invention addresses these and other issues concerning pharmaceutical compositions and formulations.

Although not limited to biopharmaceuticals, the usefulness of the present invention is well exemplified with respect to biopharmaceuticals, many of which demonstrate the problems encountered in prior-art approaches. Ensuring long-term stability and maintaining activity of biopharmaceuticals is a prevalent concern. The chemical complexity and conformational fragility of protein drugs, for example, make them highly susceptible to both physical and chemical instabilities and threaten their emergence into the marketplace. Denaturation, adsorption with container walls, aggregation, and precipitation can result from non-covalent interactions between a drug and its environment. Insulin, for instance, has been shown to adsorb onto the surfaces of glass and plastic containers, and to have interactions at air-water interfaces, leading to denaturation, aggregation and precipitation. For example, upon demonstration human growth hormone (HGH) forms dimers and higher molecular weight aggregates, and glucagon in solution has been shown to readily gel or aggregate when subjected to mechanical stress.

As a further example, researchers have distinguished nine major reaction mechanism by which proteins degrade, including hydrolysis, imide formation, deamidation, isomerization, racemization, diketopiperazine formation, oxidation, disulfide exchange, and photodecomposition. The rates of these deleterious processes depend in large measure on the protein and its environment. The primary chemical degradation products of glucagon, for example, include oxidation of Met (27), deamidation of Gln (24), and acid-catalyzed hydrolysis at Asp (9), Asp (15) and Asp (21). HGH undergoes chemical decomposition via oxidation at Met (14) and deamidation at Asn (149).

A critical challenge of product development science in the pharmaceutical industry therefore has been devising formulations that maintain the stability of the active pharmaceutical ingredient over an acceptable shelf-life. This has been especially difficult to achieve for certain API's which are unstable in solution or with respect to many common formulation processes. Developing techniques for stabilization and storage looms as a great impediment to the pharmaceutical industry. Formulation scientists have consequently used a variety of techniques to enhance the stability of API's while maintaining other important product characteristics such as biocompatibility, absorption, pharmacokinetics, efficacy and excretion.

One technique used in formulating biopharmaceuticals has been lyophilization of the biopharmaceutical solution in the presence of excipients, buffers and/or bulking agents. However, even lyophilized preparations must typically be stored under refrigeration, a requirement which is neither technically nor economically feasible in many markets and inhibits flexibility of patient use. There has therefore been a continuing demand for formulations of many biopharmaceuticals which would permit their storage at ambient temperatures. This would permit more rapid development of products, increasing flexibility in shipping, storing and carrying the drug products, and allowing introduction and use of such products in markets where refrigeration is too costly. Moreover, the increased stabilization of biopharmaceuticals would naturally improve the general use of the biopharmaceuticals where shelf life is an important consideration, whether or not refrigeration or other concerns are at issue.

The prior art use of excipients in the lyophilization of biopharmaceuticals has been directed away from inclusion of the biopharmaceuticals in single crystals in the manner of the present invention. It has been widely assumed that amorphous glasses are critical in the stabilization of biopharmaceuticals by such excipients in lyophilized form, and it has been suggested that the drug molecules must exist in amorphous regions between the crystalline domains. See, e.g., M. J. Pikal, “Freeze Drying of Proteins”, to be published in Peptide and Protein Delivery, 2^(nd) Ed., V. H., L. Lee, Marcel Dekker, Prepint, 1995. Implicit in this reasoning is the conclusion that the biopharmaceuticals could not exist as guests within single crystals.

In the process of lyophilization, typically an aqueous solution containing a biopharmaceutical with a limited amount of excipient(s) is frozen and then dried under vacuum to produce solids of sufficient stability for storage and distribution. Excipients are added to prevent blow out of the product, to provide stability during lyophilization and/or dissolution, and to enhance compatibility for parenteral use. Various excipients used with lyophilization have included salts, metal ions, polyalcohols, surfactants, reducing agents, chelating agents, other proteins, amino acids, fatty acids, and phospholipids. The more frequently used excipient include mannitol, alanine, glycine, sorbitol, lactose, arginine, and maltose. The results obtained with such excipients, however, have usually been inconsistent. Most lyophilized biopharmaceuticals are amorphous powders that have not specific structure, and as a result, the amount and location of the incorporated biopharmaceutical varies widely for the product particles. Also, they are typically readily dissolved, rendering them unsuitable for use as a sustained-release material. Further, there is no isolation of the pharmaceutical molecules from the environment or one another, leaving them susceptible to degradation by various mechanisms. Studies have shown that lyophilization of excipients can typically damage proteins rather than protect them. See, e.g., J. F. Carpenter, J. H. Crowe, “Infrared spectroscopic studies of the interaction of carbohydrates with dried proteins”, Biochemistry 1989, 28, 3916–3922; J. F. Carpenter, S. Prestrelski, T. Arakawa, “Separation of freezing- and drying-induced denaturation of lyophilized proteins by stress-specific stabilization: I. Enzyme activity and calorimetric studies,” Arch. Biochem. Biophys. 1993, 303, 456–464. K. Izutsu, S. Yoshioka, Y. Takeda, “The effects of additives on the stability of freeze-dried β-galactosidase stored at elevated temperatures”, Int. J. Pharm. 1991, 71, 137–146. K. Izutsu, S. Yoshioka, T. Teroa, “Decreased protein-stabilizing effects of cryoprotectants due to crystallization”, Pharm. Res. 1993, 10, 1232–1237.

Crystallized pharmaceuticals have been used in some instances, but there have been inherent limitations. Some API's, e.g. insulin, can be crystallized themselves, and are useful in that form for administration to patients. However, the majority of biopharmaceuticals either do not crystallize or the crystallization is very difficult, particularly on a commercial scale. Further, crystallization procedures are limited to the use of pharmaceutically-acceptable ingredients and process conditions that do not adversely affect the active pharmaceutical ingredient, thus further constraining the ability to obtain desired microcrystalline suspensions.

The fact that macromolecules are routinely isolated in sub-millimolar concentrations in a variety of crystals is known. See, e.g., K. Strupat, M. Karas, F. Hillenkamp, Int. J. Mass Spec. Ion Proc., 111, 89–102, 1991. Also, certain aromatic acids have been employed as hosts for biopolymer guests in crystals for use in matrix-assisted laser desorption ionization (MALDI) mass spectrometry, but not for the purposes of the present invention. See, Review by F. Hillenkamp, M. Karas, R. C. Beavis, B. T. Chait, Anal. Chem, 63, 1193A–1203A; S. Borman, Chem. Eng. News, 23–25, Jun. 19, 1995. However, crystallization conditions in these studies were optimized for characterization of the incorporated biopolymers. There were no investigations into optimizations that would be relevant to pharmaceutical preparations or operations such as homogeneity of the concentration of the inclusions, process scale-up, process robustness, chemical and physical stability of the preparations, suspendability in biocompatible solutions, preservative requirements and compatibility, container/closure system compatibility, and pharmacokinetic profiles.

The difficulty in obtaining suitable single crystals of some biopolymers has encouraged structural chemists to partially orient such molecules with electric, magnetic, or flow fields, by dissolution in liquid crystals or stretched gels, and as monolayers. In a similar effort, the isolation of biopolymers in a single crystal matrix has recently been studied in an effort to use such crystals for structural analysis of the biopolymers. Such isolation technique is described in “Single Crystal Matrix Isolation of Biopolymers,” J. Chmielewski, J. J. Lewis, S. Lovell, R. Zutshi, P. Savickas, C. A. Mitchell, J. A. Subramony, and B. Kahr, J. Am. Chem. Soc. 1997, 119, 10565–10566. However, this article simply demonstrates that certain biopolymers are oriented by the host lattice, and the article suggests the use of such crystals for analyzing spectral anisotropies in biological molecules which could not otherwise be crystallized. This article does not discuss or suggest the use of this technique for enhancement of stability or sustained release of pharmaceuticals, or their administration to patients. Further, the proteins studied were not a pharmaceutical interest, the crystal materials described in this article, namely phthalic acid, gentistic acid and sinapic acid, were not selected or evaluated for biocompatibility, and the crystal sizes were not optimized for particular routes of administration. Therefore, the produced crystals with included biopolymers would not be suitable for administration to patients.

Other prior art procedures have required the use of polymers that are difficult to prepare, require harsh preparation conditions that can be harmful to the API's, and yield inconsistent results. For example, U.S. Pat. No. 5,075,291 describes a process for preparing a uniformly-dispersed, pharmaceutically-active material in a crystalline sugar alcohol matrix. However, this process requires the addition of the API into a molten sugar alcohol with considerable mechanical agitation. Many API's and virtually all biopharmaceuticals would not be stable in the extreme temperature of 110° C. and the physical stresses of a high-shear vortex mixer used for agitation. The present invention does not require these extremes of temperature and physical agitation. Also, the process of the present invention slowly includes the API into the growing crystal lattice in specific growth sectors, instead of homogeneous mixing and entrapping of the active pharmaceutical ingredient in a viscous melt.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to pharmaceutical compositions comprising single crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the API's to a patient. The crystals may be coated or combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing dosage amounts of the API's. Alternatively, the crystals are prepared as depot formulations which may be administered, as by subcutaneous injection or implantation, to provide a long-term payout or sustained release of the active pharmaceutical ingredient. The present invention further provides methods for preparing the crystals and for storing and administering the active pharmaceutical ingredient either in crystal form or upon reconstitution to a solution.

Accordingly, it is an object of the present invention to provide single crystals which include API's in a growth-sector specific orientation. It is a feature of the invention that the API's are included at predictable, uniform concentrations that permit use of the crystals in formulating dosage amounts of the API's.

Another object of the present invention is to provide compositions comprising API's included in single crystals to provide improved stability and shelf-life. The active pharmaceutical ingredients may therefore be stored for extended periods of time prior to use either as crystals or as reconstituted solutions.

It is a further object of the present invention to provide single crystals with included API's to provide quick, delayed-release or sustained-release formulations for flexibility in pharmacokinetic profiles in delivery of the API's to patients.

Another object of the present invention is to provide pharmaceutical delivery units including an amount of single crystals sufficient to provide a dosage amount of the included active pharmaceutical ingredient. Alternatively, the pharmaceutical delivery units include a quantity of crystals sufficient to provide a prolonged payout of the active pharmaceutical ingredient. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants including excipients, diluents and carriers.

A further object of the present invention is to provide methods for preparing compositions comprising single crystals with growth-sector specific inclusions of API's.

It is another object of the present invention to provide methods for the storage and administration of API's utilizing inclusion of the API's within single crystals.

Other objects, features, and advantages of the present invention will be apparent to those skilled in the art from the following description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photomicrograph illustrating fluorescence of a single crystal of green fluorescent protein in α-lactose monohydrate (1.8 (h)×0.8 (w)×0.5 (d) mm³) with an idealized representation of habit. The sides of the crystal in the photomicrograph are bright due to internal reflection.

FIG. 2 is a graph of the fluorescence decay of the green fluorescent protein is 333° K. in several environments: mixed crystal in α-lactose monohydrate (triangle), saturated lactose solution (square), and lyophilized α-lactose monohydrate (diamond).

DESCRIPTION OF THE PREFERRED EMBODIMENT

For the purposes of promoting an understanding of the present invention, reference will now be made to the embodiments described hereafter. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates.

The present invention utilizes single-crystal matrix inclusion of active pharmaceutical ingredients (“API's”) to achieve advantageous storage and delivery of the API's. This invention has application to a wide range of API's to provide enhanced stability and/or delivery of the active pharmaceutical ingredients. For some applications, such as for many biopharmaceuticals, the invention is particularly advantageous in providing greater stability over time and in providing alternative delivery and sustained release formulations to patients.

The small molecule host crystals comprise a crystal lattice component which includes the API's in an oriented, growth-sector specific manner. The crystals and included API's are prepared to be pharmaceutically acceptable and pure, thereby being useful for administration to patients to be treated with the API's. As used herein, the term “pharmaceutically-acceptable” refers to sufficient quality to meet regulatory and compendial requirements for administration to humans and/or animals. The crystals provide a regular, predictable inclusion of the guest active pharmaceutical ingredient, and the crystals can consequently be used for obtaining a predetermined amount of the active pharmaceutical ingredient for delivery to a patient. In one aspect, the host crystal gradually dissolves upon contact with body tissue or fluids, and is therefore useful as a system for delivery of the active pharmaceutical ingredient into the body. Alternatively, the crystals and included active pharmaceutical ingredient may be reconstituted into a solution for administration to a patient.

The active pharmaceutical ingredient molecules are generally isolated from one another and are insulated from the environment by the host crystal. This leads to reduce susceptibility of the API to degradation, and therefore enhanced stability and shelf-life. Also, the use of appropriate host crystal compounds, or selected dosage forms, permits the design of quick, delayed, or sustained-release formulations for delivery of the active pharmaceutical ingredient. Sustained-release formulations are particularly advantageous for treatment of chronic conditions as they provide a consistent amount of drug delivery over a long period of time to improve ease of use and patient compliance in administering the API.

The crystal preferentially incorporate the active pharmaceutical ingredient on certain faces, thereby providing a growth-sector specific inclusion and orientation to the API's. As used herein, the term “growth-sector specific inclusion and orientation,” and equivalent terminology, refers to the fact that the API molecules are included primarily at certain faces of the crystal matrix. The growth-sector specific inclusion and orientation can be determined by one skilled in the art, as demonstrated in the examples herein, by fluorescence microscopy and anisotropy measurements, single crystal desorption mass spectrometry, and autoradiography of ¹⁴C-labeled material. In one embodiment, at least about 0.001% (on weight/weight (w/w) basis) of the pharmaceutical is included within specific faces of the crystal matrix, and in another embodiment at least about 0.1% (w/w) and up to about 10%. The crystal parameters, including the particular crystal lattice component for a given API, the concentration of API, the use of crystal adjuvants, and the crystallization conditions, are selected to achieve the growth-sector specific inclusion and orientation of the API within the crystals.

The method of the present invention broadly involves the including of the active pharmaceutical ingredient into the single crystal matrix formed from a pharmaceutically-acceptable crystal lattice component. As used herein, the term “included” in the crystals refers to the active pharmaceutical ingredient being chemically adsorbed within the crystal lattice as the crystal is formed. This inclusion of the active pharmaceutical ingredient molecules is distinguished from crystallization of the API molecules with one another, and from simple and random entrapment of the API molecules by the formed crystal. The crystal product of the present invention is ordered, in contrast to the amorphous material produced by other approaches. The API is incorporated in the crystal in relation to its degree of affinity for the crystal lattice molecules. The crystal lattice component is therefore selected to be both chemically and physically compatible with the API such that the API is received by the crystal during formation, and remains stable and efficacious while within the crystal and upon release therefrom.

In a typical approach, the including of the active pharmaceutical ingredient involves combining the crystal lattice component, the active pharmaceutical ingredient and a pharmaceutically-acceptable adjuvant in a liquid state. The crystal lattice component is then crystallized under pharmaceutically-acceptable conditions to form the inventive crystals. For example, one method uses spiking of the API into a saturated or supersaturated solution of the crystal lattice component in a suitable organic and/or aqueous solvent system. Alternatively, the saturated or supersaturated solution of the crystal lattice component may be spiked into the API solution. Other components may also be added to the solution, including compounds which facilitate or modify crystal growth or which are desired for incorporation in the final formulation. The solution may be seeded using any of a variety of conventional techniques.

In one approach, the solution is allowed to evaporate and/or equilibrate to cooler conditions for growth of the crystals. The crystals are then grown as the solvent is slowly evaporated away and/or the solution is cooled, with the evaporation and temperature gradient conditions being selected dependent on such factors as the solvent system and the desired crystal size. The crystals containing the active pharmaceutical ingredient are harvested from the remaining solution and are preferably washed to remove surface contamination. This procedure yields crystals which include the active pharmaceutical ingredient at a predictable concentration and facial orientation.

In accordance with the present invention, crystals are grown under pharmaceutically-acceptable conditions. As used herein, the term “pharmaceutically-acceptable conditions” refers to the use of crystal and API compounds which are pharmaceutically-pure, and for which such pharmaceutical purity is maintained in the final crystals. The crystal and API compounds are pharmaceutically pure, or have pharmaceutical purity, if they are of sufficient purity to be suitable for administration under applicable FDA or other administrative regulations regarding purity. The term pharmaceutically-acceptable conditions further refers to the user of crystallization conditions through which the API compounds retain pharmaceutical efficacy in the final crystals and upon subsequent administration to patients.

The present invention readily allows the inclusion of API's by affinity with the small host molecules in the growing crystal lattice. This overcomes many of the limitations associated with approaches. The processing involved with preparing the present crystals does not expose the API's to harsh conditions, thereby substantially reducing or avoiding the possible degradation or disruption of the structural aspects of the API which could occur with prior art techniques. The inventive crystals have an added advantage in that they do not interfere with normal analytical methodologies used for characterizing the pharmaceutical product. The small host molecules can be easily separated on the basis of molecular size, which is not the case for prior art techniques which uses polymers that interfere with analytical methodologies.

The API molecules are incorporated into the host crystals typically at rates of at least about 0.001% (w/w), preferably at least about 0.1%, and more preferably about 1% to about 10% (w/w). Alternatively, the API molecules are included at rates of at least about 0.01%, and as much as at least about 1% (w/w). The limited molar concentration of the active pharmaceutical ingredient in the host crystals means that the active pharmaceutical ingredient molecules are generally isolated from one another in the crystals. Isolation of the API molecules is particularly advantageous for those molecules, such as certain biopharmaceuticals, which could otherwise react with one another (e.g., by polymerization) or the surrounding environment. The degree of isolation can be verified by those skilled in the art using atomic force microscopy or reaction fluorescence energy techniques. The present invention has a particular application to guest-host systems in which the guest API molecules are reactive with one another, but in which these molecules are sufficiently isolated from one another in the crystals as to substantially prevent such interaction. Consequently, the invention provides containment of the API molecules in the solid state crystals and provides for the API to be comformationally stable.

The method preferably involves preparing a mixture of crystals of substantially uniform size. This may include processing of the harvested crystals, such as by grinding or milling, to reduce the crystals to a substantially uniform size. Greater uniformity can be achieved by sorting the processed crystals, such as by sieving. A preferred method further includes obtaining crystals which have a substantially uniform concentration of pharmaceuticals, for example, about 1% (w/w) of pharmaceuticals, that do not vary between crystals by more than 10 percent.

The method of the present invention may further include formulating the crystals into pharmaceutical preparations. For example, the collected crystals may optionally be coated with a suitable composition. Coated or uncoated crystals may be blended with one or more pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. The blended crystals and adjuvant(s) are then formulated into pharmaceutical delivery units. In one embodiment, each unit includes a predetermined amount of the pharmaceutical. Alternatively, the crystals are combined in a delivery unit intended to deliver multiple or sustained dosing of the API over a period of time, such as by subcutaneous implantation of the delivery unit. A further aspect of the method of the present invention involves reconstituting the crystals to liquid form. In accordance with this method, the harvested crystals are dissolved in a suitable diluent for the crystal lattice component. The dissolution of the crystals releases the API from the crystals. The resulting solution may include other adjuvants, such as excipients, diluents or carriers, and the mixture is formulated under conventional procedures to desired delivery forms. In a particular aspect of the present invention, the crystals are used to store the pharmaceutical for a period of times, such as at least one month, or at least one year, and the crystals are subsequently dissolved to use the active pharmaceutical ingredient.

The present invention involves the use of any of a wide variety of pharmaceutically-acceptable host crystal systems that can incorporate API's in a growing crystal lattice. The crystal lattice component is selected to be compatible with the guest API, and to be suited to the use of the resulting formulation for storage and administration. Selection of the crystal lattice component will involve consideration of such factors as affinity for the API, crystal size distribution and morphology, and desired pharmaceutical concentration and delivery rate, as well as other factors well known in the art of pharmaceutical delivery systems. The crystal systems must consistently incorporate the guest active pharmaceutical ingredient in terms of concentration and placement within the crystal lattice. The crystals also must grow under conditions which will not degrade or otherwise adversely effect the viability of the active pharmaceutical ingredient.

Preferred host crystal materials are those that have a high affinity for the included API. It appears that the oriented inclusion of the API's is related to the affinity between the crystal lattice component and the API. The affinity between these materials is therefore important in obtaining the desired inclusion of the API's, and also permits control of the inclusion based upon this affinity. For example, the concentration of the pharmaceutical in a crystal can be controlled by selecting the host component to have an affinity for the API which yields the desired inclusion rate. Also, mixtures of host materials, or of host materials and other excipients, can be used to provide an affinity yielding the desired inclusion level. In one aspect of the present invention, the API's are incorporated at levels of at least about 0.001% (w/w of guest:host), more preferably at least about 0.1% (w/w).

The preferred host crystal materials will also be very stable and readily crystallizable, and will maintain their “order” or crystal morphology when including a guest molecule, particularly large biomolecules. The use of particular host crystal components will also depend on such factors as how small or large the crystals can be produced and how readily they dissolve. For various routes of administration, it is desirable to have very small crystals (e.g., pulmonary), moderately sized crystals (e.g., injectable), or very large crystals (e.g., implantation and long term payout). The useful crystal sizes will therefore vary accordingly, ranging from submicron to millimeter sizes. In one aspect of the present invention the preferred crystals are in the order of 5–100 microns in size.

The useful host crystal systems are therefore diverse, and include various small molecule crystal systems which meet the desired criteria. Examples of pharmaceutically-acceptable crystal lattice components include sugars, polyhydroxy alcohols, single and polyamino acids, vitamins, salts, metals, preservatives, aromatic compounds especially aromatic acids, purified natural products, and polymers. Preferred crystal lattice components include, for example, sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, and potassium citrate. Also, compatible mixtures of these materials are also useful, and can be selected to obtain the desired rate of inclusion of the pharmaceutical, or to achieve desired characteristics, such as dissolution rate and pharmacokinetic profile, for the product crystals.

The crystal lattice components are selected to achieve the desired pharmacokinetics for the final crystals. As pertains to the present invention, the term “pharmacokinetics” is used to refer to the profile of the delivery of active pharmaceutical ingredient from the crystals into the circulatory system. This will depend primarily on the concentration of the active pharmaceutical ingredient in the crystals, as well as parameters of the active pharmaceutical ingredient itself. While given crystal lattice components will have associated inclusion and dissolution characteristics, these can be modified by including other crystal lattice components, other API's, or a variety of excipients. Thus, single crystals having two different, co-crystallied lattice components will typically be characterized by pharmacokinetic profiles different from crystals prepared with either of the crystal lattice components alone. Similarly, including excipients or other API's will provide altered rates of inclusion or dissolution for the resulting crystals, providing an associated modification in the pharmacokinetic profile for the resulting crystals.

In a related aspect, the present invention involves the use of mixtures of crystals having different pharmacokinetics in order to achieve desired payout profiles. For example, a pharmaceutical product can be obtained by combining two different types of crystals, one type of crystal using a first crystal lattice component characterized by a first pharmacokinetic profile, and the second type of crystal using a second crystal lattice component characterized by a second pharmacokinetic profile. The mixture of crystals will give a payout of API that is different from either of the individual payouts for the two crystal types.

The included API's are similarly diverse, limited simply by the requirements of compatibility with the host crystal and the crystal growth conditions. The active pharmaceutical ingredient cannot be unacceptably degraded or otherwise adversely affected by the conditions under which the crystals are formed. Also, the active pharmaceutical ingredient should remain stable for an extended period of time while included within the host crystal, and pharmaceutically efficacious upon release from the crystal.

Given the foregoing criteria, examples of API's useful in accordance with the present include: antibiotics (such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin), fluoxetine, raloxifene, olanzapine, and nizatidine. A more complete list of API's useful in accordance with the present invention would include those identified in the following Table A.

TABLE A Marketed Recombinant Protein Products Tissue Plasminogen Activator, T-PA Product name: Activase (Generic name: Altepase) Produced by: Genentech Indication: Human use, Acute myocardial infarction Date of approval: November 87, Patent expires on December 2000. Formulation: Intravenous injection. Lyophilized powder which is reconstituted with sterile water (supplied) to 1 mg/mL and results in a final pH of 7.3. Can not be reconstituted with preserved water due to precipitation. The 1 mg/mL solution can be diluted 1:1 with 0.9% NaCl or D5W and help for 8 hours at room temperature. TPA is incapable with preservatives. Ingredients 100 mg vial 50 mg vial 20 mg vial T-PA 100 mg 50 mg 20 mg L-Arginine 3.5 g 1.7 g 0.7 g Phosphoric acid 1 g 0.5 g 0.2 g Polysorbate 80 <11 mg <4 mg <1.6 mg Vacuum No Yes Yes Expression System: Mammalian cell line (Chinese Hamster Ovary cells) Refolding Conditions: Structure: Glycoprotein of 527 amino acids, sequence from human melanoma cell line, activity of 580,000 IU/mg. Additional Information: Sales > $100 million. Cost of therapy $2,750 (100 mg). Interferon Gamma-1b Product name: Actimmune Produced by: Genentech Indication: Human use, chronic granulomatous disease Date of approval: December 1990 Formulation: Single dose solution formulation (0.5 mL), subcutaneous injection. Each 0.5 mL contains 100 μg interferon gamma-1b, 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate-20 in sterile water. Expression System: E. coli Refolding Conditions: Post-Transitional Modifications: Structure: Single chain; Human sequence, 140 amino acids, 16,465 molecular weight, non-covalent dimeric form in solution, activity or 30 million units/mg. Additional Information: 14% injection site irritation vs. 2% in placebo. Cost $140 for 50 μg. Interferon alfa-n3 (natural source, not recombinant) Product name: Alferon N Produced by: Interferon Science (New Brunswick, NJ) Indication: Human use, Genital Warts Date of approval: June 90 Formulation: Preserved solution formulation (each mL contains 5 million IU of interferon alfa-n3 in phosphate buffered saline containing 3.3 mg phenol and 1 mg human albumin). Injected intralesional twice weekly for up to 8 weeks (50 μL injected into each wart, 500 μL total dose per treatment). Expression System: Natural source - human leukocytes which are exposed to an avian virus in order to produce interferon. Refolding Conditions: None Structure: Approximately 166 amino acids with a molecular weight ranging from 16 to 27 kDa, specific activity of 20,000 IU/m° or greater. Additional Information: Cost $142 per mL. Beta Interferon 1a Product name: Avonex Produced by: Biogen (Cambridge, MA) Indication: Human use, Multiple Sclerosis Date of approval: May 95 Formulation: Lyophilized powder (stored refrigerated or at 25° C. for < 30 days) which is reconstituted with sterile water (supplied, 1.1 mL) to 30 μg/mL beta interferon 1a, 15 mg/mL human albumin, 5.8 mg/ml NaCl, 5.7 mg/ml dibasic Na phosphate, 1.2 mg/ml monobasic sodium phosphate, and has a pH of approximately 7.3 (recon solution is stable for 6 hours at refrigerated temperatures). Weekly intramuscular injection by patient or doctor (dosed for 1–2 years in clinical trials). Expression System: Mammalian cells (Chinese Hamster Ovary cells) Refolding Conditions: Structure: Glycoprotein (single N-linked complex carbohydrate), 166 amino acids with a predicted molecular weight of 22,500 daltons, human sequence, has a specific activity of 200 million units per mg protein. Additional Information: Cost $180 per vial (33 μg) Interferon beta-1b Product name: Betaseron Produced by: Berlex Laboratories (Wayne, NJ and Chiron, Emeryville, CA) Indication: Human use, Multiple Sclerosis Date of approval: July 93. Formulation: Lyophilized product (stored refrigerated) which is reconstituted with 0.54% NaCl (supplied) to 0.25 mg/mL interferon beta-1b, 12.5 mg/mL human albumin, 12.5 mg/ml dextrose, and has a pH of approximately 7.3 (recon solution is stable for 3 hours). Injected subcutaneously every other day (chronic use). Expression System: E. coli Refolding Conditions: Structure: 165 amino acids with an approximate molecular weight of 18,500 daltons, human sequence but with a serine or cysteine substitution at residue 17. Recombinant form does not contain the carbohydrate moiety found in the natural material. Has a specific activity of 32 million units per mg protein. Additional Information: Sales > $500 million. Cost of therapy is $13,140 (based on 0.25 mg/injection, dose every other day for 1 year; equals 46 mg protein). Interferon alfa-2b Product name: Intron A Produced by: Schering-Plough (Madison, NJ) Indication: Human use, Hairy cell leukemia, genital warts, Hepatitis, Melanoma, Kaposi's sarcoma Date of approval: June 86 Formulation: Comes in a lyophilized and a solution formulation. The lyophilized formulations when reconstituted with 0.9% benzyl alcohol (supplied) contains either 0.015, 0.025, 0.05, 0.90, or 0.125 mg/ml. Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, and 1 mg/ml human albumin. The solution formulations contain either 0.05, 0.114, or 0.125 mg/mL Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, 1 mg/ml human albumin, 1.2 mg/mL methylparaben, and 0.12 mg/ml propylparaben. These formulations be injected intramuscular, subcutaneous, or intralesional. All formulations and reconstituted products are stored at refrigerated temperatures. Expression System: E. coil Refolding Conditions: Structure: Water soluble protein a molecular weight of 19,271 daltons. The Interferon alfa-2b gene is derived from human leukocytes. Additional Information: Sales > $500 Million. Cost of therapy is $16,445 (5 mlllion units every day for 1 year, this is equal to 9 mg protein). Specific activity is 200 million units per mg protein Interferon alfa-2a Product name: Roferon-A Produced by: Hoffmann-La Roche (Nutley, NJ) Indication: Human use, Hairy cell leukemia, Kaposi's sarcoma, myelogenous leukemia Date of approval: June 1986 Formulation: Multi-use and lyophilized formulation indented for intramuscular or subcutaneous administration. Multi-use formulation contains either 0.015, 0.045, 0.090, 0.18 mg/mL Interferon alfa-2a, 9 mg/ml NaCl, 5 mg/ml human albumin, and 3 mg/ml phenol. The lyophilized formulation reconstituted with 3 mL of supplied diluent (6 mg/ml NaCl, 3.3 mg/ml phenol) consists of 0.03 mg/ml Interferon alfa-2a, 9 mg/ml NaCl, 1.67 mg/ml human albumin, and 3.3 mg/ml phenol. Expression System: E. coli (tetracycline promoter). Refolding Conditions: Structure: Protein of 165 amino acids having a molecular weight of 19,000 daltons Additional Information: Cost of therapy is $59,200 (28 mg protein over 1 year). Specific activity is 200 million international units per mg protein. Human Growth Hormone (Somatropin) Product name: BioTropin Produced by: Bio-Technology General (Iselin, NJ) Indication: Human use, Growth Deficiency Date of approval: May 95 Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Human Growth Hormone (Somatropin) Product name: Genotropin Produced by: Pharmacia and Upjohn (Kalamazoo, MI) Indication: Human use, Growth Deficiency Date of approval: August 95 Formulation: Expression System: Refolding Conditions: Structure: Additional Information: Human Growth Hormone (Somatropin) Product name: Humatrope Produced by: Eli Lilly (Indianapolis, IN) Indication: Human use, Growth Deficiency Date of approval: March 87 Formulation: Lyophilized product which is reconstituted with sterile water containing 0.3% m-cresol, 1.7% glycerin (supplied) to 2 mg/mL hGH and has a final pH of approximately 7.5, subcutaneous or intramuscular administration. Each 5 mg lyophilized vial contains 5 mg hGH, 25 mg mannitol, 1.13 mg dibasic sodium phosphate, and 5 mg glycine. Expression System: E. coli. Refolding Conditions: Structure: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary- derived material. Additional Information: Cost $210 per 5 mg hGH. Human Growth Hormone (Somatropin) Product name: Norditropin Produced by: Novo Nordisk (Princeton, NJ) Indication: Human use, Growth Deficiency Date of approval: July 91 Formulation: Expression System: Refolding Conditions: Post-Transitional M difications: Structure: Additional Information: Human Growth Hormone (Somatropin) Product name: Nutropin and Nutropin AQ Produced by: Genentech Indication: Human use, Growth Deficiency Date of approval: March 1994 Formulation: Lyophilized product which is reconstituted with bacteriostatic water (0.9% benzyl alcohol, supplied) to 5 mg/mL hGH and has a final pH of approximately 7.4, subcutaneous or intramuscular administration. Each 5 mg lyophilized vial contains 5 mg hGH, 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg monobasic and 1.3 mg dibasic), and 1.7 mg glycine. Expression System: E. coli, expressed with a leading secretion signal precursor which directs the protein to the plasma membrane of the cell where the sequence is removed and the native protein is secreted into the periplasm so that the protein if folded appropriately as it is synthesized Refolding Conditions: None, expressed folded in E. coli. Structure: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary- derived material. Additional Information: Cost $420 per 10 mg hGH. β-Glucocerebrosidase (imiglucerase) (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) Product name: Cerezyme Produced by: Genzyme (Cambridge, MA) Indication: Human use, Gaucher's disease Date of approval: May 94 Formulation: Lyophilized product (212 units glucocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysorbate-80; stored refrigerated) is reconstituted with 5.1 mL of sterile water, final pH is approximately 6.1. The reconstituted material is combined with 100 to 200 mL of 0.9% NaCl and administered intravenously. Expression System: Mammalian cell culture (Chinese Hamster Ovary cells) Refolding Conditions: Structure: Monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites, molecular weight is 60,430 daltons. Recombinant protein differs from human placental glucocerebrosidase by a arginine substituted for histidine at position 495 and the glycosylation sites have been modified to terminate in mannose sugars (which are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease). Additional Information: Orphan Drug, sales > $100 million, Cost of therapy is $351,130 (1 year). Hepatitis B Surface Antigen Product name: Engerix-B Produced by: SmithKline Beechman (Philadelphia, PA) Indication: Human use, Hepatitis B Date of approval: September 89 Formulation: Suspension (20 μg/mL hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal, 9 mg/ml NaCl, 1.7 mg/ml sodium phosphates). Intramuscular administration. Expression System: A portion of the hepatitis B virus gene, coding for hepatitis B surface antigen, in cloned into yeast (Saccharomyces cerevisiae) Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Formulation contains no more than 5% yeast proteins. Hepatitis B Surface Antigen Product name: Recombivax HB Produced by: Merck (Whithouse Station, NJ) Indication: Human use, Hepatitis B prevention Date of approval: July 1986 Formulation: Suspension (10 μg/ml hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal). Intramuscular administration. Expression System: A portion of the hepatitis B virus gene, coding for hepatitis B surface antigen, in cloned into yeast (Sacccharomyces cerevisiae) Refolding Conditions: Structure: Additional Information: Formulation contains no more than 1% yeast proteins. Erythropoietin (rEPO) Product name: Epogen or Epoetin alfa (Also sold under the name Procrit by Ortho Biotech but manufactured by Amgen) Produced by: Amgen (Thousand Oaks, CA) Indication: Human use, Anemia Date of approval: June 89, Patent expires in 2004 (December). Formulation: Two solution formulations, single dose and multi-dose. Single-dose is preservative free and each mL contains 2000, 3000, 4000, or 10000 units Epogen, 2.5 mg human albumin, 5.8 mg sodium citrate, 5.8 mg NaCl, and 0.06 mg citric acid in water for injection, pH 6.9 +/− 0.3. The preserved multi- dose product contains 10,000 units Epogen, 2.5 mg human albumin, 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid and 1% benzyl alcohol per mL of solution, pH is 6.1 +/− 0.3. Both solutions are stored refrigerated. Expression System: Mammalian cell Refolding Conditions: Structure: Glycoprotein of 165 amino acids having a molecular weight of 30,400 daltons, sequence identical to that of the human protein. Additional Information: Sales > $500 million, Cost $120 for 10,000 units. Human Insulin Product name: Hurnulin Produced by: Eli Lilly (Indianapolis, IN) Indication: Human use, Diabetes Date of approval: October 82 Formulation: Expression System: E. Coli Refolding Conditions: Structure: Additional Information: Sales > $500 Million. Human Insulin Product name: Novolin Produced by: Novo Nordisk (Princeton, NJ) Indication: Human use, Diabetes Date of approval: July 91 Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: LysPro Human Insulin Product name: Hurnulog Produced by: Eli Lilly (Indianapolis, IN) Indication: Human use, Diabetes Date of approval: June 1996 Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) Product name: Leukine Produced by: Immunex (Seattle, WA) Indication: Human use, Bone marrow transplantation, Hodgkin's Disease, Leukemia Date of approval: March 91 Formulation: Lyophilized solution which is reconstituted with sterile water (stored at refrigerated temperatures for < 6 hours) or 0.9% benzyl alcohol (can be stored for < 20 days at refrigerated temperatures) and administered intravenous. After reconstitution, the lyophilized single use product contains either 0.25 mg/mL or 0.50 mg/mL GM-CSF, 40 mg/ml mannitol, 10 mg/ml sucrose, and 1.2 mg/ml tromethamine (final pH is 7.4 +/− 0.3). The reconstituted solution is then diluted into a 0.9% NaCl bag for IV administration (note if final GM-CSF is below 0.01 mg/mL add human albumin to 0.1% to prevent adsorption to the IV bag. Expression System: Yeast (S. Cerevisiae) Refolding Conditions: None, expressed folded. Structure: Glycoprotein of 127 amino acids characterized by 3 primary molecular species having molecular masses of 19,500, 16800, and 15500 daltons. The primary sequence differs from natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from native. Additional Information: Specific activity is 5 × 10⁷ colony forming units per mg protein. Sargramostim is the proper name for yeast-derived recombinant GM-CSF. Cost for a 0.5 mg GM-CSF vial is $178. G-CSF (Granulocyte Colony Stimulating Factor) Product name: Neupogen Produced by: Amgen (Thousand Oaks, CA) Indication: Human use, Neutropenia, bone marrow transplantation, anemia Date of approval: February 91 Formulation: Single-use solution formulation containing 0.3 mg/mL G-CSF, 10 mM sodium acetate, 5% mannitol, and 0.004% Tween-80 at a pH of 4. The product is to be stored at refrigerated temperatures and no more than 24 hours at room temperature. If required, Neupogen can be diluted with D5W (no not dilute with saline at any time; product may precipitate), at concentrations below 5 to 15 μg/mL, add human albumin to 2 mg/mL to prevent adsorption to IV bag. Expression System: E. coli. Refolding Conditions: Structure: A 175 amino acid protein with a molecular weight of 18,800 daltons. The protein has an amino acid sequence identical to the human protein except for an additional N-terminal methionine (necessary for expression in E. coli). The human protein is glycosylated but the recombinant Neupogen is not. Additional Information: Sales > $500 million. Filgrastim is the name give to recombinant methionyl human G-CSF. Cost of therapy (lung cancer) is $2,130 (4.2 mg protein over 14 days). Specific activity is 30 million units per mg protein. Satumomab Pendetide Product name: OncoScint CR/OV Produced by: Cytogen (Princeton, NJ) Indication: Human use, Colorectal and ovarian cancers Date of approval: December 92 Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Interleukin-2 Product name: Proleukin (generic name: Aldesieukin) Produced by: Chiron (Emeryville, CA) Indication: Human use, Renal cell carcinoma Date of approval: May 1992 Formulation: Single-use lyophilized formulation which is reconstituted with 1.2 mL sterile water and administered intravenously. Each reconstituted product contains 1.1 mg/mL Proleukin, 50 mg/ml mannitol, and 0.18 mg/ml dibasic sodium phosphate (pH is 7.5 +/− 0.3). Lyophilized product is stored at refrigerated temperatures, reconstituted product is stable up to 48 hours at refrigerated to room temperatures, but should be stored in refrigerator due to lack of preservatives. Addition of preservatives results in increased aggregation, addition of human albumin alters pharmacology. Expression System: E. coli (tetracycline promoter). Refolding Conditions: Structure: Proleukin has a molecular weight of 15,300 daltons and differs from the natural human protein (is not glycosylated, the N-terminal alanine is removed, and has a serine substituted for the free cysteine at position 125) Additional Information: Specfic activity is 18 million international units per 1.1 mg protein. Cost is $395 per 1.3 mg protein. Somatrem Product name: Protropin Produced by: Genentech (S. San Francisco, CA) Indication: Human use, Growth deficiency Date of approval: October 1985, patent expired on October 1992. Formulation: Lyophilized formulation which is reconstituted with 0.9% benzyl alcohol (supplied) and administered intramuscular or subcutaneous. The lyophilized vial contains 5 mg Somatrem, 40 mg mannitol and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic) and is reconstituted with 1 to 5 mL of 0.9% benzyl alcohol. The lyophilized product is stored at refrigerated temperature, the reconstituted product is good for 14 days at refrigerated temperatures. Expression System: E. coli. Refolding Conditions: Structure: Contains 192 amino acids with molecular weight of 22,000 daltons. Identical to human sequence but contains an extra methionine at the N-terminus. Additional Information: Sales > $100 million. Cost of therapy is $13,110 (1 year, 313 mg protein) DNase (deoxyribonuclease I) Product name: Pulmozyme Produced by: Genentech (S. San Francisco, CA) Indication: Human use, Cystic fibrosis Date of approval: December 1993 Formulation: Inhalation solution (aerosol mist produced by a compressed air driven nebulizer system). Comes in a single-use 2.5 mL ampule containing 1.0 mg/mL DNase, 0.15 mg/mL calcium chloride dihydrate, and 8.77 mg/ml sodium chloride, at a pH of 6.3. The solution is stored at refrigerated temperatures and should not be exposed to light. Expression System: Mammalian cells (Chinese hamster Ovary cells) Refolding Conditions: Structure: Glycoprotein of 260 amino acids having a molecular weight of 37,000 daltons. The primary sequence is identical to that of the native human enzyme. Additional Information: Sales > $100 Million. Cost is $32 for 2.5 mg of protein (1 ampule) M-CSF (Macrophage-Colony Stimulating Factor) Product name: Leucomax (generic name: Molgramostim) Produced by: Indication: Human use, Date of approval: FDA unapproved Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Epoetin Beta (Erythropoietin) Product name: Marogen Produced by: Indication: Human use, Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Polyribonucleotide Product name: Ampligen Produced by: Indication: Human use, Date of approval: FDA Unapproved Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Human Serum Albumin Product name: Produced by: Indication: Human use, Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Septomonab? Product name: Gentoxin Produced by: Indication: Human use, Date of approval: Not FDA approved Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: Protein Product name: Produced by: Indication: Human use, Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information: APPROVED BIOTECHNOLOGY DRUGS AND VACCINES Product Product Name Company Category Indication Cornvax ™ Merck recombinant vaccination of infants beginning at two months of age Haemophilus b Whitehouse Station, NJ. vaccine against both invasive Haemophilus influenzae type b conjugate diseases (Hib) and hepatitis B (October 1996) (meningococcal protein conjugate) and hepatitis b (recombinant) vaccine Engerix-B ® SmithKline Beecham recombinant hepatitis B (September 1989) hepatitis B vaccine Philadelphia, PA vaccine (recombinant) EPOGEN ® Amgen erythropoietin treatment of anemia associated with chronic renal Epoetin alfa Thousand Oaks, CA falure, including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovir ®-treated HIV-infected patients (June 1998); treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996) PROCRIT ® Ortho Biotech erythropoietin treatment of anemia associated with chronic renal Epoetin alfa Raritan, NJ failure, including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovi ®-treated HIV-infected patients (December 1990); treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996) [PROCRIT was approved for marketing under Amgen’s epoetin alfa PLA. Amgen manufactures the product for Ortho Biotech J Under an agreement bewteen the two companies, Amgen licensed to Ortho Pharmaceutical the U.S. rights to epoetin alfa for indications for human use excluding dialysis and diagnostics. Genotropin ™ Pharmacia & Upjohn human short stature in children due to growth hormone somatropin Kalamazoo, MI growth deficiency (August 1995) (rDNA origin) hormone for injectiojn Gerel ® Serono Laboratories growth evaluation of the ability of the somatotroph of the human growth Norwell, MA factor pituitary gland to secrete growth hormone hormone (December 1990); pediatric growth hormone releasing factor deficiency (October 1997) Genal-F ® Serono Laboratories recombinant female infertility (September 1997) recombinant human Norwell, MA fertility follicle-stimulating hormone hormone (r-FSH) Humalog ™ Eli Lilly recombinant diabetes (June 1996) insulin lispro Indianapolis, IN insulin Humatrope ® Eli Lilly human human growth hormone deficiency in children somatropin Indianapolis, IN growth (March 1987) (rDNA origin) hormone for injection Humulin ® Eli Lilly recombinant diabetes (October 1982) human insulin Indianapolis, IN insulin (recombinant DNA origin) infergen ® Amgen interferon treatment of chronic hepatitis C viral infection interferon alfacon-1 Thousand Oaks, CA (October 1997) Intron ® A Schering-Plough interferon hairy cell leukemia (June 1986); genital warts interferon alfa-2b Madison, NJ (June 1988); AIDS-related Kaposi's sarcoma (recombinant) (November 1988); hepatitis C (February 1991); hepatitis B (July 1992); malignant melanoma (December 1995); follicular lymphoma in conjunction with chemotherapy (November 1997) KoGENate ® Bayer Corporation, clotting treatment of hemophilia A (February 1993) antihemophiliac Pharmaceutical Division factor factor West Haven, CT (recombinant) Leukine ™ Immunex colony autologous bone marrow transplantation (March 1991); sargramostim Seattle, WA stimulating neutropenia resulting from chemotherapy in acute (GM-CSF) factor myelogenous leukemia (September 1995); allogeneic bone marrow transplantation (November 1995); peripheral blood progenitor cell mobilization and transplantation (December 1995) MyoScint ® Centocor MAb myocardial infarction imaging agent (July 1996) imiclromab pentetate Malvern, PA Neumega ® Genetics Institute MAb prevention of severe chemotherapy-induced oprelvekin Cambridge, MA thrombocytopenia (November 1997) NEUPOGEN ® Amgen colony chemotherapy-induced neutropenia (February 1991); Filgrastim Thousand Oaks, CA stimulating autologeous or allogeneic bone marrow transplantation (rG-CSF) factor (June 1994); chronic severe neutropenia (December 1994); support peripheral blood progenitor cell transplantation (December 1995) Norditropin ® Novo Nordisk human treatment of growth failure in children due to somatropin Pharmaceuticals growth inadequate of growth hormone secretion (May 1995) (rDNA origin) Princeton, NJ hormone for injection Novolin ® 70/30 Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1991) 70% NPH human Pharmaceuticals insulin insulin isophane Princeton, NJ suspension & 30% regular, human insulin injection (recombinant DNA origin) Novolin ® I. Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1991) Lente ®, human Pharmaceuticals insulin insulin zinc Princeton, NJ suspension (recombinant DNA origin) Novolin ® N Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1991) NPH, human Pharmaceuticals insulin insulin isophane Princeton, NJ suspension (recombinant DNA origin) Novolin ® R Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1991) regular, human Pharmaceuticals insulin insulin injection Princeton, NJ (recombinant DNA origin) Nutropin ® Genentech human growth failure in children due to chronic renal somatropin S. San Francisco, CA growth insufficiency, growth hormone inadequacy in children for injection hormone (March 1994); Turner's syndrome (December 1996); growth hormone inadequacy in adults (December 1997) Nutropin AQ ™ Genentech human growth failure in children due to chronic renal somatropin S. San Francisco, CA growth insufficiency, growth hormone inadequacy in children (liquid) hormone (December 1995); Turner's syndrome (December 1996); growth hormone inadequacy in adults (December 1997) OncoScint ™ CYTOGEN MAb detection, staging and follow-up of colorectal and CR/OV Princeton, NJ ovarian cancers (December 1992) satumomab pendetide ORTHOCLONE Ortho Biotech MAb reversal of acute kidney transplant rejection OKT ®3 Raritan, NJ (June 1986); reversal of heart and liver transplant muromonab-CD3 rejection (June 1993) Proleukin ® Chiron interleukin renal cell carcinoma (May 1992); metastatic melanoma aldesleukin Emeryville, CA (January 1998) (interleukin-2) ProstaScint ® CYTOGEN MAb detection, staging and follow-up of prostate capromab Princeton, NJ adenocarcinoma (October 1996) pentetate Protropin ® Genentech human human growth hormone deficiency in children somatrem S. San Francisco, CA growth (October 1985) for injection hormone Pulenozyme ® Genentech recombinant cystic fibrosis (December 1993); management of domase alpha, S. San Francisco, CA DNase advanced cystic fibrosis (December 1996) recombinant Recombinate ™ Baxter Healthcare/ clotting hemophilia A (December 1992) antihemophilic Hyland Division factor factor recombinant Glendale, CA (rAHF) Genetics Institute Cambridge, MA RECOMBIVAX HB ® Merck recombinant hepatitis B prevention (July 1986) hepatitis B vaccine Whitehouse Station, NJ vaccine (recombinant), MSD Refludan ™ Hoechst Marion Roussel recombinant heparin-induced thrombocytopenia type II lepirudin Kansas City, MO anticoagulant (March 1998) [rDNA] for injection Regranex ® Orthro-McNeil growth lower extremity disbetic neuropathic ulcers becaplemin Pharmaceuticals factor (December 1997) Raritan, NJ ReoPro ® Centocor MAb anti-platelet prevention of blood clots in the setting of abciximab Malvern, PA high-risk percutaneous transluminal coronary angioplasty Eli Lilly (December 1994); refractory unstable angina when Indianapolis, IN percutaneous coronary unstable angina when (November 1997) Retevase ™ Boehringer Mannheim tissue treatment of acute myocardial infarction (October 1996) reteplase Gaithersburg, MD plasminogen Centocor factor Malvern, PA Rituxan ® Genentech MAb treatment of relapsed or refractory low-grade or rituximab S. San Francisco, CA follicular CD20-positive B-cell non-Hodgkin's IDEC Pharmaceuticals lymphoma (November 1997); San Diego, CA Roferon ®-A Hoffmann-La Roche interferon hairy cell leukemia (June 1986); AIDS-related Kaposi's interferon alfa-2a, Nutley, NJ sarcoma (NPvember 1988); chronic myelogenous recombinant leukemia (November 1995); hepatitis C (November 1996) Saizen ® Serona Laboratories human pediatric growth hormone deficiency (October 1996) somatropin Norwell, MA growth (rDNA origin) hormone for injection Serostim ™ Serono Laboratories human treatment of AIDS-associated catabolism/wasting somatropin Norwell, MA growth (August 1996); pediatric HIV failure to thrive (rDNA origin) hormone (February 1998) for injection Verluma ® Boehringer ingelheim MAb detection of small-cell lung cancer (August 1996) nofetumomab Ridgefield, CT NeoRx Seattle, WA Vistide ® Gilead Scienced nucleotide cytomegalovirus retinitis in AIDS patients (June 1996) cidofovir injection Foster City, CA analogue Zenapax ® Hoffman-La Roche MAb prevention of acute kidney transplant rejection daclizumab Nutley, NJ (December 1997) The content of this survey has been obtained through government and industry sources based on the latest information. The information may not be comprehensive. For more specific information about a particular product, contact the individual company directly. PhRMA internet adress: http://www.pharma.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 1998 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded is proper credit is given.

Pharmaceutical Research and Manufacturers of America 1100 Fifteenth Street, NW Washington, D.C. 20005 http://www.phrma.org Printed on recycled paper. 4/98 Biotechnology Medicines in Development Product Product Development Name Company Category Indication Status AIDS/HIV INFECTION AND RELATED CONDITIONS AD-439 and Tanox Biosystems MAb HIV infection, AIDS Phase II AD-519 Houston, TX combination AD-439 MAb, Tanox Biosystems MAb HIV infection, AIDS Phase II anti-HIV to V3 Houston, TX loop of gp120 protein; neutralizing antibody AD-519 MAb, Tanox Biosystems MAb HIV infection, AIDS Phase II anti-HIV to C4 Houston, TX region of gp120 protein; neutralizing antibody Alferon LDO ® Interferon Sciences interferon AIDS-related complex, AIDS Phase I/II interferon alfa-n3 New Brunswick, NJ Alferon N Interferon Sciences interferon HIV infection Phase III injection ® New Brunswick, NJ (see also infectious diseases) interferon alfa-n3 co-infection (HIV/HCV) Phase II ALVAC-MN Pasteur Merieux Connaught vaccine HIV infection Phase II 12-TMG Lyons, France (vCP205) Virogenetics Albany, NY Ampligen ® Hemispherx Biopharma interferon HIV infection Phase II New York, NY (see also cancer, infectious diseases, other) autologous gene- SyStemix gene therapy HIV infection Phase I modified Palo Alto, CA hematopoietic stem cells gene therapy Cell Genesys gene therapy HIV infection Phase II Foster City, CA Hoechst Marion Roussel Kansas City, MO gp120 VaxGen vaccine AIDS Phase II vaccine S. San Francisco, CA HIV-IT(V) Chrion Viagene gene therapy asymptomatic HIV-1 infection Phase II Retrovector ™ San Diego, CA HIV-1 1118 enc/rev retroviral vector HIV vaccine Chiron vaccine AIDS Phase II (gp120) Emeryville, CA interleukin-10 Schering-Plough interleukin HIV disease Phase I (IL-10) Madison, NJ (see also autoimmune, digestive, heart, neurologic, respiratory, skin) ISIS 2922 Isis Pharmaceuticals antisense cytomegalovirus retinitis Phase III fornivirsen Carlsbad, CA ISIS 13312 Isis Pharmaceuticals antisense cytomegalovirus retinitis Phase I Carlsbad, CA Leukine ™ Immunex colony adjuvant to AIDS therapy, Phase II sargramostim Seattle, WA stimulating HIV infection, prevention of (GM-CSF) factor infection in HIV patients (see also cancer) memantine Neurobiological AIDS dementia complex and Phase II Technologies AIDS-related neuropathic pain Richmond, CA (see also diabetes) MPL ® Ribi ImmunoChem vaccine AIDS Phase I immunomodulator Hamilton, MT (see also infectious diseases) vaccine NEUPOGEN ® Amgen colony treatment and prevention of application Filgrastim Thousand Oaks, CA stimulating neutropenia in HIV patients submitted (rG-CSF) factor (see also cancer, respiratory) Ovidrel ® Ares-Serono and recombinant Kaposi's sarcoma, AIDS-related Phase I/II recombinant Serono Laboratories gonadotropin hypogonadism human chorionic Norwell, MA (see also infertility) gonadotropin (r-hCG) PEG interleukin-2 Chiron interleukin HIV infection in combination Phase II Emeryville, CA with Retrovir ® PMPA Gilead Sciences nucleotide HIV infection, AIDS Phase II Foster City, CA analogue Preveon ™ Gilead Sciences nucleotide HIV infection, AIDS Phase III adefovir dipivoxil Foster City, CA analogue PRO 367 Progenics Pharmaceuticals HIV infection Phase I Tarrytown, NY PRO 542 Progenics Pharmaceuticals HIV infection Phase I Tarrytown, NY Proleukin ® Chiron interleukin HIV infection in combination Phase II/III aldesleukin Emeryville, CA with Retrovir ® (interleukin-2) (see also cancer) Remune Immune Response Corp. immune- HIV seropositive Phase III HIV-1 immunogen Carlsbad, CA based therapy retroviral vector Chiron gene therapy HIV infection Phase I/II with 2 ribozymes Emeryville, CA TBC-38 Therion Biologics vaccine AIDS prevention Phase I (vaccinia virus Cambridge, MA expressing HIV genes env, gag and pal) AUTOIMMUNE DISORDERS adensoine National Cancer Institute gene therapy severe combined Phase I deaminase- Bethesda, MD immunodeficiency NCI TRIAL transduced autologous CD34+ PBC or umbilical cord/ placental blood cells adenosine National Cancer Institute gene therapy severe combined Phase I deaminase- Bethesda, MD immunodeficiency NCI TRIAL transduced T cells AnergiX ™-RA Anergen functional rheumatoid arthritis Phase I Redwood City, CA antigenics immuno- therapy AnervaX ™ Anergen peptide rheumatoid arthritis Phase II Redwood City, CA vaccine Avakine ™ Centocor MAb rheumatoid arthritis Phase III chimeric anti-TNF Malvern, PA (see also digestive) antibody CD40 ligand Biogen MAb lupus, immune thromobocytopenic Phase II antibody Cambridge, MA purpura clenoliximab IDEC Pharmaceuticals MAb rheumatoid arthritis Phase II San Diego, CA SmithKline Beecham Philadelphia, PA ConXn ™ Connetics recombinant scleroderma Phase II relaxin Palo Alto, CA human protein Enbrel Immunex recombinant rheumatoid arthritis Phase III tumor necrosis Seattle, WA soluble factor (TNF) Wyeth-Ayerst Laboratories receptor receptor Philadelphia, PA h5G1.1 Alexion Pharmaceuticals MAb lupus, rheumatoid arthritis Phase I/II New Haven, CT IDEC-131 IDEC Pharmaceuticals MAb systemic lupus erythermatosus Phase I humanized MAb San Diego, CA IL-2 fusion protein Seragen fusion severe rheumatoid arthritis Phase I/II DAB₁₈₅IL-2 Hopkinton, MA protein (see also cancer, skin) interleukin-10 Schering-Plough interleukin rheumatoid arthritis Phase II (IL-10) Madison, NJ (see also AIDS/HIV, digestive, heart, neurologic, respiratory, skin) IR 501 Immune Response Corp. vaccine rheumatoid arthritis Phase II therapeutic Carlsbad, CA vaccine ISIS 2302 Isis Pharmaceuticals antisense rheumatoid arthritis Phase II Carlsbad, CA (see also digestive, skin, transplantation) MDX-33 Medarex MAb autoimmune diseases, idiopathic Phase I Annandale, NJ thrombocytopenic purpura ORTHOCLONE Ortho Biotech MAb treatment of CD4-mediated Phase II OKT4A Raritan, NJ autoimmune diseases (see also transplantation) Quadrakine Schering-Plough interleukin rheumatoid arthritis Phase I interleukin-4 Madison, NJ (IL-4) SMART ™ Anti-CD3 Protein Design Labs MAb autoimmune diseases Phase I HuM291 Mountain View, CA (see also transplantation) BLOOD DISORDERS CPC-111 Cypros Pharmaceuticals cellular sickle cell disease Phase II Carlsbad, CA therapy (see also heart) Factor VIII Transkaryotic Therapies gene therapy hemophilia A Phase I Cambridge, MA GA-EPO Hoechst Marion Roussel erythropoietin anemia associated with Phase II Kansas City, MO chronic renal failure Transkaryotic Therapies Cambridge, MA Kogenate-N Bayer clotting hemophilia A Phase III tFVIII Berkeley, CA factor NovoSeven ® Novo Nordisk clotting treatment of hemophilia A & B with Phase III recombinant factor Pharmaceuticals factor and without antibodies against Vita Princeton, NJ factors VIII/IX Optro ™ Somatogen recombinant oxygen-carrying agent and Phase II recombinant human Boudler, CO human alternative to red blood caell hemoglobin hemoglobin transfusion (rHb1.1) stimulation of red blood cell Phase I formation ReFacto ® Genetics Institute clotting hemophilia A Phase III recombinant factor Cambridge, MA factor VIII YM-337 MAb Yamanouchi USA MAb platelet aggregation Phase I White Plains, NY Protein Design Labs Mountain View, CA CANCER AND RELATED CONDITIONS 1311-ChTNT-1/8 Techniclone MAb malignant glioma Phase I Tustin, CA Aastrom ™ Aastrom Biosciences cellular cancer immunosuppression/ Phase II Cell Production Ann Arbor, MI therapy blood and immune system System recovery for patients receiving stem and progenitor ablative chemotherapy cell expansion from bone marrow and umbilical cord blood Actimmune ® National Cancer Institute interferon colon, lung, ovarian, prostate Phase II interferon Bethesda, MD cancers, melanoma NCI TRIAL gamma-1b Genentech S. San Francisco, CA AFP-Scan ™ Immunomedics MAb extent of disease staging of liver Phase II technetium-99m- Morris Plains, NJ and germ cell cancers FAb′ fragment (germ cell) allogeneic SyStemix cellular advanced leukemia, lymphona, Phase I hematopoietic Palo Alto, CA therapy myelodysplastic syndromes stem cell transplantation Allovectin-7 Vical gene therapy advanced metastatic melanoma, Phase II DNA/lipid complex San Diego, CA non-resectable squamous cell encoding HLA-87 carcinoma of the head and neck antigen ALT Cellcor cellular metastatic renal cell carcinoma Phase III (autolymphocyte Newton, MA therapy (kidney cancer) completed therapy) CYTOGEN Princeton, NJ ALVAC-87.1 National Cancer Institute gene therapy melanoma Pahse I Bethesda, MD NCI TRIAL ALVAC-CEA-87.1 National Cancer Institute gene therapy advanced adenocarcinomas Phase I Bethesda, MD NCI TRIAL ALVAC-CEA National Cancer Institute vaccine advanced cancers Phase I vaccine Bethesda, MD NCI TRIAL ALVAC-IL-12 National Cancer Institute vaccine melanoma Phase I vaccine Bethesda, MD NCI TRIAL Pasteur Merieux Connaught Lyons, France Ampligen ® Hemispherx Biopharma interferon renal cancer Phase I/II New York, NY (see also AIDS/HIV, infectious diseases, other) anti-cancer T-cell Cell Genesys gene therapy colon cancer Phase I/II gene therapy Foster City, CA anti-idiotype Novartis Pharmaceuticals MAb cancer Phase I monoclonal East Hanover, NJ antibody anti-Tac(Fv)-PE38 National Cancer Institute MAb + toxin leukemia, lymphoma Phase I immunotoxin Bethesda, MD NCI TRIAL anti-transferrin National Cancer Institute MAb advanced, refractory solid tumors Phase I receptor Bethesda, MD NCI TRIAL MAb anti-VEGF Genentech MAb cancer Phase I humanized MAb S. San Francisco, CA autologous SyStemix cellular hematopoietic reconstitution in Phase I/II hematopoietic Palo Alto, CA therapy patients with multiple myleoma, stem cells for non-Hodgkin's lymphoma, autologous breast cancer hematopoietic transplantation autologous peptide- National Cancer Institute cellular advanced solid tumors Phase I specific activated Bethesda, MD therapy NCI TRIAL lymphocytes autologous National Cancer Institute gene therapy breast cancer, myeloma Phase I transduced CD34+ Bethesda, MD NCI TRIAL bone marrow and peripheral blood stem cells Avicidin ® Janssen Pharmaceutics MAb colorectal, lung, prostate cancers Phase II MAb conjugate Titusville, NJ NeoRix Seattle, WA Avicine ™ AVI BioPharma vaccine colorectal, pancreatic cancers Phase II CTP-37 Portland, OR Avonex ® Biogen interferon glioma Phase II interferon beta-1A Cambridge, MA (see also neurologic) B7 transfected National Cancer Institute vaccine melanoma Phase I allogeneic Bethesda, MD NCI TRIAL melanoma cell vaccine BEC2, anti-idiotype ImClone Systems vaccine melanoma, small-cell lung cancer Phase I MAb Somerville, NJ Betaseron ® National Cancer Institute interferon non-small-cell lung cancer Phase III recombinant Bethesda, MD (see also neurologic) NCI TRIAL beta interferon-1b Berlex Laboratories Wayne, NJ bispecific Chiron MAb cancer Phase I antibody Emeryville, CA C225, anti-EGFR ImClone Systems MAb epidermal growth factor receptor Phase II chimeric MAb Somerville, NJ positive cancers Campath 1H LeukoSite Mab chronic lymphocytic leukemia in clinical Cambridge, MA trials carcinoembryonic National Cancer Institute vaccine breast, gastrointestinal tract, Phase I antigen peptide-1 Bethesda, MD lung cancers NCI TRIAL vaccine CEACide ™ Immunomedics MAb colorectal cancer Phase II humanized Morris Plains, NJ anti-CEA antibody (hMN14) CEA-Scan ™ Immunomedics Mab extent of disease staging of breast Phase II technetium-99m- Morris Plains, NJ cancer arcitumomab (breast) CEA-Scan ™ Immunomedics MAb extent of disease staging of lung Phase III technetium-99m- Morris Plains, NJ cancer arcitumomab (lung) CEAVac ™ Titan Pharmaceuticals vaccine colorectal cancer Phase II anti-idiotype S. San Francisco, CA antibody vaccine cell therapy CytoTherapeutics cellular cancer pain, untreatable/unrelieved Phase II Providence, RI therapy by other forms of treatment Cereport ™ Alkermes recurrent malignant brain tumor Phase III (RMP-7) Cambridge, MA and carboplatin chemotherapy- Genetix gene therapy treatment of cancer patients Phase I/II resistant Rye, NY requiring chemotherapy bone marrow chimeric MAb National Cancer Institute Mab melanoma, neuroblastoma Phase II 14, 18 Bethesda, MD NCI TRIAL CM 101 CarboMed cancer Phase I/II Brentwood, TN CMA-676 Wyeth-Ayerst Laboratories Mab relapsed acute myelogenous Phase II/III Philadelphia, PA leukemia CMB-401 Wyeth-Ayerst Laboratories MAb ovarian cancer Phase I/II Philadelphia, PA colon cancer Immune Response Corp. vaccine colon cancer Phase I/II cell line Carlsbad, CA vaccine Sidney Kimmel Cancer Center San Diego, CA CP-358, 774 OSI Pharmaceuticals cellular cancer Phase I Uniondale, NY therapy Pfizer New York, NY CT-2584 Cell Therapeutics ovarian, prostate cancer, Phase I Seattle, WA sarcoma cytosine deaminase GenVec gene therapy colon cancer Phase I gene-adenoviral Rockville, MD vector DA/Hu(gamma).4 Chiron Viagene gene therapy metastatic melanoma Phase I [hiFN-y(V)] San Diego, CA Retrivector ™ hiFN-y retroviral vector DA/Hu(gamma), 15- Chiron Viagene gene therapy stage IV Phase I transduced San Diego, CA malignant melanoma autologous tumor cells and interferon- gamma expressing transduced autologous tumor cells (combination therapy) DA/Hu(gamma), 15- Chiron Viagene gene therapy disseminated Phase I transduced San Diego, CA malignant melanoma autologous tumor cells; ITAT dariplestim Searle growth factor mobilization of peripheral Phase III Skokie, IL blood stem cells dendritic cell Dendreon cellular advanced prostate cancer Phase II/III therapy Mountain View, CA therapy multiple myeloma Phase I E/A lipid complex Targeted Genetics gene therapy breast, head and neck, ovarian Phase I (rgDCC-E/A) Seattle, WA cancers EGF fusion protein Seragen fusion protein non-small-cell lung cancer Phase I/II DAB₃₈₉EGF Hopkinton, MA EPREX ® National Cancer Institute erythropoietin neuroblastoma Phase II erythropoietin Bethesda, MD NCI TRIAL Ortho Biotech Raritan, NJ ERB-38 National Cancer Institute fusion protein advanced stage solid tumors Phase I immunotoxin Bethesda, MD NCI TRIAL fusion protein (recombinant) Ewing's sarcoma Natioanl Cancer Institute vaccine sarcoma Phase I and alveolar Bethesda, MD NCI TRIALS rhabdomyosarcoma peptide vaccine FLT3 ligand National Cancer Institute growth factor melanoma, renal cell cancer Phase I Bethesda, MD NCI TRIAL Immunex Seattle, WA G3139 Genta antisense cancer Phase I San Diego, CA gamma interferon Chiron gene therapy cancer Phase I gene therapy Emeryville, CA Gastrimmune ™ Aphton vaccine colorectal, pancreatic, stomach Phase I/II neutralizing G17 Woodland, CA cancers hormone (see also digestive) GeneVax ® Centocor vaccine colorectal cancer Phase I gene vaccine Malvern, PA GLI-328 Genetic Therapy gene therapy glioblastoma multiforme Phase III Gaithersburg, MD GM-CSF cellular Powderject Vaccines vaccine melanoma, sarcoma Phase I cancer vaccine Madison, WI GMK Bristol-Myers Squibb vaccine prevent recurrence following surgery Phase III ganglioside Princeton, NJ to remove primary melanoma antigen Progencis Pharmaceuticals Tarrytown, NY gp100 adenovirus National Cancer Institute vaccine melanoma Phase I vaccine Bethesda, MD NCI TRIAL Genzyme Molecular Oncology Cambridge, MA gp100 peptide National Cancer Institute vaccine melanoma Phase I vaccine Bethesda, MD NCI TRIAL GVAX ™ Cell Genesys vaccine prostate, lung cancers, melanoma Phase I/II cancer vaccine Foster City, CA HER-2/neu National Cancer Institute vaccine breast, colorectal, ovarian, Phase I peptide vaccine Bethesda, MD prostate cancers NCI TRIAL Herceptin ™ Genentech MAb breast cancer Phase III trastuzumab S. San Francisco, CA completed (anti-HER-2 humanized MAb) HPV 16, E6 and E7 National Cancer Institute vaccine cervical cancer Phase I peptide vaccine Bethesda, MD NCI TRIAL HPV E7 lipopeptide National Cancer Institute vaccine cervical cancer Phase I vaccine Bethesda, MD NCI TRIAL Cytel San Diego, CA HPV vaccine Medimmune vaccine cervical cancer Phase I Gaithersburg, MD (see also infectious disease) SmithKline Beecham Philadelphia, PA HSPPC-96 Antigenics heat shock melanoma, pancreatic, Phase I (autologous New York, NY portein renal cell cancers tumor derived) human growth Transkaryotic Therapies gene therapy cancer cachexia (muscle wasting) Phase I hormone Cambridge, MA IDEC-In88 IDEC Pharmaceuticals Mab non-Hodgkin's B-cell lymphoma Phase I/II San Diego, CA IDEC-Y288 IDEC Pharmaceuticals MAb non-Hodgkin's B-cell lymphoma Phase I/II San Diego, CA Leucotropin Cangene colony mobilization of peripheral blood Phase III GM-CSF Mississauga, Ontario stimulating stem cells in patients with factor adjuvant breast cancer Leukine ™ Immunex colony prophylaxis and treatment of application sargramostin Seattle, WA stimulating chemotherapy-induced neutropenia, submitted (GM-CSF) factor prophylaxis of chemotherapy-induced neutropenia in acute myelogenous leukemia (see also AIDS/HIV) Lervectin Vical gene therapy prostate cancer, renal cell carcinoma, Phase I DNA/lipd complex San Diego, CA melanoma, sarcoma encoding IL-2 LP 2307 LIDAX Pharmaceuticals vaccine malignant melanoma Phase I/II La Jolla, CA LR-3001 Inex Pharmaceuticals antisense chronic myelogenous leukemia Phase I Hayward, CA in accelerated phase or blast crisis LYM-T Techniclone MAb lymphoma Phase II/III Tustin, CA Lymphocide ™ Immunomedics MAb non-Hodgkin's B-cell lymphoma Phase I/II anti-CD22 Morris Plains, NJ humanized MAb LymphoScan ™ Immunomedics MAb extent of disease staging of Phase III technetium-99m- Morris Plains, NJ non-Hodgkin's B-cell lymphoma, bectumomab detection of residual disease (lymphoma) following radiation/chemotherapy Mab Glaxo Wellcome Mab lung, prostate cancers Phase II Rsch, Triangle Park, NC MART-1 National Cancer Institute vaccine melanoma Phase I adenvirus Bethesda, MD NCI TRIAL vaccine Genzyme Molecular Oncology Cambridge, MA MART-1 National Cancer Institute vaccine metastatic melanoma Phase I melanoma Bethesda, MD NCI TRAIL vaccine MDRx1 ™ Titan Pharmaceuticals gene therapy enable high-dose chemotherapy Phase I S. San Francisco, CA with reduced side effects MDX-447 Medarex Mab head and neck, renal cancers Phase I/II bispecific antibody Annandale, NJ MDX-H210 Medarex MAb breast, colorectal, kidney, ovarian, Phase I/II bispecific antibody Annandale, NJ prostate cancers Melacine ® Ribi ImmunoChem vaccine stage IV melanoma with interferon Phase III melanoma Hamilton, MT alpha completed theraccine Ribi ImmunoChem vaccine stage II melanoma in patients with Phase III (therapeutic Hamilton, MT no evidence of disease to prevent vaccine Southwest Oncology Group recurrence following surgery to San Antonio, TX remove primary disease myeloid progenitor Human Genome Sciences interleukin chemoprotection Phase I inhibitory factor-1 Rockville, MD myeloma-derived National Cancer Institute vaccine multiple myeloma Phase I idiotypic antigen Bethesda, MD NCI TRIAL vaccine NEUPOGEN ® Amgen colony acute myelogenous leukemia application Filgrastim Thousand Oaks, CA stimulating (see also AIDS/HIV, respiratory) submitted (rG-GSF) factor Oncaspar ® Enzon first-line treatment of acute in clinical PEG-L-asparaginase Piscataway, NJ lymphoblastic leukemia (ALL) trials Rhone-Poulenc Rorer adult ALL non-Hodgkin's lymphoma, Titusville, NJ chronic lymphocytic leukemia Oncolym ® Techniclone MAb malignant glioma Phase I Tustin, CA Oncoltad ® PR CYTOGEN MAb targeted radiotherapy for prostate Phase II CYT-356-Y-90 Princeton, NJ malignancies OncoScint ® CYTOGEN MAb detection, staging and follow-up Phase II CR/OV Princeton, NJ of breast cancer satumomab pendetide ONYX-015 Onyx Pharmaceuticals oncolytic p53 deficient cancers Phase I/II Richmond, CA virus therapy p53 and RA5 National Cancer Institute vaccine solid tumors Phase I vaccine Bethesda, MD NCI TRIAL p53 tumor Schering-Plough gene therapy lung cancer Phase II suppressor gene Madison, NJ solid tumors that carry the Phase I p53 gene mutation or deletion Panorex ® Centocor MAb adjuvant therapy for post-operative Phase III edrecolomab Malvern, PA colorectal cancer peripheral blood National Cancer Institute gene therapy ovarian cancer Phase I lymphocytes Bethesda, MD NCI TRIAL transduced with a gene encoding a chimeric T-cell receptor Proleukin ® Chiron interleukin acute myelogenous leukemia, Phase II/III aldesleukin Emeryville, CA non-Hodgkin's lymphoma (interleukin-2) (see also AIDS/HIV) promegapoletin Searle growth factor adjunctive hematopoietic therapy Phase I Skokie, IL following chemotherapy Prostrac Therion Biologics vaccine prostate cancer Phase I/II recombinant Cambridge, MA vaccinia virus RA5 5-17 peptide National Cancer Institute vaccine solid tumors Phase I vaccine Bethesda, MD NCI TRIAL rCEA Vaccine Protein Sciences vaccine breast, colon cancers Phase I recombinant Meriden, CT carcinoembryonic antigen Rebi ® Serono Laboratories interferon colorectal cancer Phase III recombinant Norwell, MA (see also infectious diseases, interferon beta-1a neurologic) non-small-cell lung cancer Phase I/II recombinant human Genetics Institute interleukin cancer Phase I/II interleukin-12 Cambridge, MA (see also infectious diseases) (rhIL-12) Wyeth-Ayerst Laboratories Philadelphia, PA retroviral vector Chiron gene therapy melanoma Phase I with tumor necrosis Emeryville, CA factor gene rf-gp100 Therion Biologics vaccine melanoma Phase I (recombinant Cambridge, MA fowlpox virus) rF-MART-1 Therion Biologics vaccine melanoma Phase I (recombinant Cambridge, MA fowlpox virus) RIGScan ® CR49 Neoprobe MAb colorectal cancer application 125 I-cc49 MAb Dublin, OH submitted Rituxan ® National Cancer Institute Mab leukemia, lymphoma Phase II rituximab Bethesda, MD NCI TRIAL IDEC Pharmaceuticals San Diego, CA Roferon ®-A Hoffmann-La Roche interferon malignant melanoma adjuvant Phase III interferon alfa-2a, Nutley, NJ recombinant rV-gp100 Therion Biologics vaccine melanoma Phase I (recombinant Cambridge, MA vaccinia virus) rV-MART-1 Therion Biologics vaccine melanoma Phase I (recombinant Cambridge, MA vaccinia virus) Serostim ™ Serono Laboratories human cancer cachexia Phase I/II somatropin Norwell, MA growth (see also other) (rDNA origin) hormone for injection Sigoslx ® Ares-Serono and interleukin hematological conditions Phase I/II recombinant Serono Laboratories (myelodysplastic syndromes, cancer) interleukin-6 Norwell, MA (r-IL-6) SMART ™ M195 Protein Design Labs MAb acute myeloid leukemia Phase II/III HuM195 Mountain View, CA acute promyelocytic leukemia Phase II advanced myeloid leukemia Phase I (with Bismuth-213) stem cell factor Amgen stem cell adjunct to chemotherapy application Thousand Oaks, CA factor submitted SU101 SUGEN PDGF- malignant glioma Phase III Redwood City, CA receptor prostate cancer Phase II tyrosine solid tumors Phase I/II kinase inhibitor SUS416 SUGEN angiogenesis solid tumors Phase I Redwood City, CA inhibitor TBC CEA Therion Biologics vaccine colorectal and lung cancers Phase I/II (vaccinia virus Cambridge, MA expressing carcinoembryonic antigen) TCell-HDM Coulter Cellular Therapies cellular cancer Phase I/II Boston, MA therapy Theratope ® Biomira vaccine breast cancer Phase II synthetic Edmonton, Alberta completed carbohydrate Chiron therapeutic Emeryville, CA vaccine thrombopoietin Genentech erythropoietin thrombocytopenia related to cancer Phase II S. San Francisco, CA treatment Thyrogen ® Genzyme detection and treatment of application recombinant human Cambridge, MA thyroid cancer metastases submitted thyroid-stimulating hormone TNT Techniclone MAb non-Hodgkin's B-cell lymphoma Phase II/III Tustin, CA solid tumors Phase I TriAB ™ Titan Pharmaceuticals vaccine breast cancer Phase II anti-idiotype S. San Francisco, CA antibody vaccine TriGEM ™ Titan Pharmaceuticals vaccine small-cell lung cancer, melanoma Phase I anti-idiotype S. San Francisco, CA antibody vaccine urate oxidase Sanoli recombinant prophylaxis for chemotherapy- Phase III (recombinantly- New York, NY enzyme related hyperuricemia, treatment produced enzyme) of cancer-related hyperuricemia vaccine-CEA National Cancer Institute vaccine advanced colorectal cancer Phase I 180KD Bethesda, MD NCI TRIAL vaccine Therion Biologics Cambridge, MA Vaxid Vical vaccine B-cell and mantle cell lymphomas Phase I anti-idiotype DNA San Diego, CA vaccine Xerecept ™ Neurobiological brain tumor edema Phase II human Technologies corticorropin- Richmond, CA releasing factor (hCRF) Zenapax ® Hoffmann-La Roche Mab certain blood cancers Phase II daclizumab Nutley, NJ (see also eye, neurologic, skin, Protein Design Labs transplantation) Mountain View, CA DIABETES AND RELATED CONDITIONS Beta Kline Genzyme Tissue Repair growth chronic diabetic foot ulcers Phase II transforming growth Cambridge, MA factor factor-beta 2 BetaRx-H VivoRx cellular insulin-dependent diabetes Phase I encapsulated Santa Monica, CA therapy human islets BetaRx-P VivoRx cellular insulin-dependent diabetes Phase I encapsulated Santa Monica, CA therapy procine islets BetaRx-Pr VivoRx cellular insulin-dependent diabetes Phase I encapsulated Santa Monica, CA therapy proliferated human islets Glucagen ™ Novo Nordisk recombinant hypoglycemia Phase III recombinant human Pharmaceuticals human (see also digestive) glucagen Princeton, NJ protein (protein) glucagen Eli Lilly recombinant to treat severe hypoglycemic events application for injection Indianapolis, IN human in patients with diabetes and to aid submitted (rDNA origin) protein in gastrointestinal diagnostic procedures insulinotropin Scios type 2 diabetes Phase II Mountain View, CA mernantine Neurobiological painful diabetic neuropathy Phase II Technologies (see also AIDS/HIV) Richmond, CA nerve Genentech growth diabetic peripheral neuropathy Phase III growth factor S. San Francisco, CA factor pirnagedine Alteon diabetic progressive kidney disease, Phase III Ramsey, NJ diabetic end-stage kidney disease Genentech (see also neurologic) S. San Francisco, CA pramlintide Amylin Pharmaceuticals human improved metabolic control, Phase III San Diego, CA amylin which includes glucose, weight analog and lipid profiles in type 1 and insulin-using type 2 diabetes rDNA insulin Inhale Therapeutic Systems recombinant diabetes Phase II Palo Alto, CA insulin Trovert ™ Sensus human diabetes-related illnesses Phase II Austin, TX growth (see also growth disorders) hormone DIGESTIVE DISORDERS Avakine ™ Centocor Mab Crohn's disease application chimeric anti-TNF Malvern, PA (see also autoimmune) submitted antibody Gastrimmune ™ Aphton vaccine gastroesphageal reflux disease, Phase I/II neutralizing G17 Woodland, CA peptic and nonsteroidal hormone anti-inflammatory drug ulcers (see also cancer) Glucagen ™ Novo Nordisk recombinant gastrointestinal motility inhibition Phase III recombinant Pharmaceuticals human (see also diabetes) human glucagen Princeton, NJ protein (protein) interleukin-10 Schering-Plough interleukin Crohn's disease, ulcerative colitis Phase II (IL-10) Madison, NJ (see also AIDS/HIV, autoimmune, heart, neurologic, respiratory, skin) ISIS 2302 Isis Pharmaceuticals antisense Crohn's disease, ulcerative colitis Phase II Carlsbad, CA (see also autoimmune, skin, transplanatation) LDP-02 Genentech MAb inflammatory bowel disease Phase II S. San Francisco, CA LeukoSite Cambridge, MA LeukoScan ® Immunomedics MAb inflammatory bowel disease Phase II sulesomab Morris Plains, NJ (see also infectious diseases) Neurnega ® Genetics Institute interleukin Crohn's disease Phase II recombinant human Cambridge, MA interleukin-11 recombinant ICOS pancreatitis Phase II platelet activating Bothell, WA (see also respiratory) factor- acetyllhydrolase (rPAF-AM) EYE CONDITIONS BPD-MA QLT Photo Therapeutics age-related macular degeneration Phase III verteporfin Vancouver, British Columbia MDX-RA Medarex Mab prevention of secondary cataract Phase III immunotoxin Annandale, NJ Zenapax ® Hoffmann-La Roche Mab uveitis Phase I/II daclizumab Nutley, NJ (see also cancer, neurologic, skin, Protein Design Labs transplantation) Mountain View, CA GENETIC DISORDERS AAV CFTR Targeted Genetics gene therapy cystic fibrosis Phase I gene therapy Seattle, WA (see also respiratory) CFTR/adenovirus Genzyme gene therapy cystic fibrosis Phase I vector Cambridge, MA CFTR/lipid Genzyme gene therapy cystic fibrosis Phase I vector Cambridge, MA ex vivo stem cells/ Genzyme gene therapy Gaucher's disease Phase I retrovirus vector Cambridge, MA GR2134878 Glaxo Wellcome gene therapy cystic fibrosis Phase I/II Rsch, Triangle Park, NC Megabios Burlingame, CA GV-10 GenVec gene therapy cystic fibrosis Phase I Rockville, MD HP-3 Milkhaus Laboratory signalling cystic fibrosis Phase II Boxford, MA Neuprex ™ XOMA recombinant cystic fibrosis exacerbations Phase I recombinant human Berkeley, CA human (see also infectious diseases, other) bactericidal/ protein permeability- increasing protein (rBPI-21) Pulmozyme ® Genentech recombinant early intervention in cystic fibrosis Phase III domase alpha, S. San Francisco, CA DNase recombinant x-galachosidase A Transkaryotic Therapies enzyme Fabry' disease Phase I Cambridge, MA GROWTH DISORDERS pralmorelin Wyeth-Ayerst Laboratories human adult growth hormone deficiency Phase I (GPA-748) Philadelphia, PA growth hormone ProLease ® hGH Alkermes human growth hormone deficiency Phase III Cambridge, MA growth in children Genentech hormone S. San Francisco, CA Saizen ® Serono Laboratories human management of adults with growth Phase III somatropin Norwell, MA growth hormone disorder, intrauterine (rDNA origin) hormone growth retardation in children for injection (see also other) Trovert ™ Sensus human acromegaly Phase II Austin, TX growth (see also diabetes) hormone HEART DISEASE AcuTect ™ Diatide peptide detection of carotid thrombus Phase II Tc-99m apcitide Londonderry, NH anti-CD18 Genentech MAb acute myocardial infarction Phase II humanized MAb S. San Francisco, CA BioByPant ™ CenVec gene thearpy cardiovascular disease, Phase I therapeutic Rockville, MD including cardiac artery disease angiogenesis and peripheral vascular disease, (VEGF) either as an adjunct or alternative to existing surgical approaches such as cardiac artery approaches such as cardiac artery bypass grafts and angioplasty Biostent ™ NeoRx reduction of restinosis (vascular Phase I Seattle, WA remodeling) following balloon angioplasty Capiscint Centocor MAb atherosclerotic plaque imaging Phase I Malvern, PA agent Corsevin ™ M Centocor MAb thrombolytic complications of Phase I 12D10-Fab Malvern, PA percutaneous transluminal Corvas coronary angioplasty, coronary San Diego, CA arterial starts, disseminates intravascular coagulation CPC-111 Cypros Pharmaceuticals cellular coronary bypass surgery Phase II Carlsbad, CA therapy (see also blood) factor VIIa Corvas deep vein thrombosis, pulmonary Phase I inhibitors San Diego, CA embolism, unstable angina, myocardial infarction FIBLAST ® Scios growth peripheral vascular disease, Phase II trafermin Mountain View, CA factor coronary artery disease Wyeth-Ayerst Laboratories (see also neurologic) Philadelphia, PA gene therapy Collateral Therapeutics gene therapy stable exertional angina Phase I/II San Diego, CA growth factor Chiron growth coronary artery disease Phase I Emeryville, CA factor h5G1.1-SCFV Alexion Pharmaceuticals cardiopulmonary Phase II (recombinant) New Haven, CT bypass-associated inflammation Enzon using SCD ® technology Piscataway, NJ Hu23F2G ICOS MAb myocardial infarction Phase II MAb Bothell, WA (see also neurologic, other) integrillin ™ COR Therapeutics percutaneous transluminal application eptifibatide S. San Francisco, CA coronary angioplasty, submitted (IIb/IIIa platelet Schering-Plough unstable angina aggregation Madison, NJ acute myocardial infarction Phase II inhibitor) interleukin-10 Schering-Plough interleukin ischemic reperfusion injury Phase I (IL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, neurologic, respiratory, skin) lanoteplase Bristol-Myers Squibb t-PA acute myocardial infarction Phase III Princeton, NJ LR-3280 Inex Pharmaceuticals antisense cardiovascular restinosis Phase II Vancouver, BC Schwarz Pharma Milwaukee, WI MH1-Fab′ American Biogenetic MAb in vivo imaging agent for the Phase I/II imaging agent Sciences detection of cardiovascular Boston, MA thrombosis MPL ®-C Ribi ImmunoChem prevention/amelioration of Phase II immunomodulator Hamilton, MT cardiac ischemia reperfusion injury Natrecor ® BNP Scios acute congestive heart failure Phase III Mountain View, CA completed/ application submitted cardiovascular pulmonary surgery Phase I Novastan ® Texas Biotechnology heparin-induced application argatroban Houston, TX thrombocytopenia submitted thrombosis syndrome ReoPro ® Centocor MAb unstable angina Phase III abciximab Malvern, PA (see also neurologic) Eli Lilly acute myocardial infarction Phase II Indianapolis, IN rhAntithrombin III Genzyme control of blood clotting during Phase II (recombinant) Cambridge, MA coronary artery bypass surgery completed TNK Genentech t-PA acute myocardial infarction Phase III (secondpgeneration S. San Francisco, CA t-PA) TP10 T Cell Sciences recombinant heart attack Phase I Needham, MA soluble (see also respiratory, transplantation) receptor VEGF Genentech growth coronary artery disease Phase I S. San Francisco, CA factor VEGF 121 Scios growth cardiovascular disorders Phsae I (vascular Mountain View, CA factor endothelial growth factor) Xubix ™ Genentech acute coronary syndrome Phase III sibratiban S. San Francisco, CA oral IIb/IIIa antagonist INFECTIOUS DISEASES adefovir dipivoxil Gilread Sciences nucleotide hepatitis B Phase II Foster City, CA analogue Alferon N Gel ® Interferon Sciences interferon human papillornavirus infections Phase II interferon alfa-n3 New Brunswick, NJ Alferon N Interferon Sciences interferon chronic hepatitis C infections Phase III injection ® New Brunswick, NJ (see also AIDS/HIV) interferon alfa-n3 genital warts Phase II Ampligen ® Hemispherx Biopharma interferon hepatitis Phase I/II New York, NY (see also AIDS/HIV, cancer, other) anti-tumor necrosis Chiron MAb sepsis Phase II/III factor MAb Emeryville, CA Campylobacter Antex Biologics cellular traveler's diarrhea Phase II vaccine Gaithersburg, MD vaccine (Campylobacter infections) CMV vaccine Chiron vaccine cytomegalovirus infection Phase II Emeryville, CA DTaP vaccine Chiron vaccine diphtheria, tetanus, Phase III Emeryville, CA acellular pertussis Epstein-Barr virus Aviron recombinant prevention of Epstein-Barr virus Phase I vaccine Mountain View, CA subunit infection (Cause of mononucleosis SmithKline Beecham vaccine infection) Philadelphia, PA genital herpes Glaxo Wellcome vaccine genital herpes Phase I vaccine Rsch. Triangle Park, NC Helicobacter Artex Biologics cellular peptic ulcers Phase I vaccine Gaithersburg, MD vaccine (Helicobacter pylori infections) hepatitis A Chiron vaccine hepatitis A Phase III vaccine Emeryville, CA hepatitis B DNA Powderject Vaccines DNA hepatitis B prevention Phase I vaccine Madison, WI vaccine hepatitis B vaccine SmithKline Beecham vaccine treatment of hepatitis B Phase II (recombinant) Philadelphia, PA herpes simplex SmithKline Beecham vaccine prevention of herpes simplex Phase III vaccine Philadelphia, PA infection (recombinant) HPV vaccine Medimmune vaccine genital warts Phase I Gaithersburg, MD (see also cancer) SmithKline Beecham Philadelphia, PA human Protein Design Labs MAb liver transplantation due to Phase I/II anti-hepatitis B Mountain View, CA chronic hepatitis B infection completed antibody (OST 577) Intron ® A Schering-Plough interferon pediatric hepatitis B, self-injectable application interferon alfa-2b Madison, NJ closing system for hepatitis C submitted (recombinant) (see also cancer) hepatitis C(PEG-Intron A) Phase III intron ® A/ Schering-Plough interferon relapsed hepatitis C application Rebelol ™ Madison, NJ submitted interferon alfa-2b naive hepatitis C(not previously Phase III (recombinant)/ treated with interferon) ribavirin hepatitis C (PEG-intron A/Rebetol) Phase I LeukoScan ® immunomedics MAb diagnosis of osteomyelitis, application sulesomab Morris Plains, NJ infected prosthesis, appendicitis submitted (see also digestive) Lyme borreliosis Pasteur Merieux Connaught vaccine Lyme disease Phase III protein vaccine Swiftwater, PA Lyme disease SmithKline Beecham vaccine prevention of Lyme disease application vaccine Philadelphia, PA submitted (recombinant) MAK 195F Knoll Pharmaceutical Mab sepsis Phase III Mt. Olive, NJ MEDI-491 Mediummune vaccine B 19 parvovirus-induced Phase I parvovirus Gaithersburg, MD miscarriage and anemia B 19 vaccine meningococcus C Chiron vaccine meningococcus C Phase II vaccine Emeryville, CA MPL ® Ribi ImmunoChem vaccine infectious diseases in clinical immunomodulator Hamilton, MT (see also AIDS/HIV) trials (25+ antigens for adult and pediatric applications) Neuprex ™ XOMA recombinant meningococcemia Phase III recombinant human Berkeley, CA human (see also genetic, other) bactericidal/ protein antibiotic adjuvant in Phase II permeability- intra-abdominal infections increasing protein (rBPI-21) Protovir ™ Protein Design Labs MAb cytomegalovirus infections in Phase II human anti-CMV Mountain View, CA bone marrow transplant patients completed antibody Rebii ® Serono Laboratories interferon viral infections Phase II/III recombinant Norwell, MA (see also cancer, neurologic) interferon beta-1a recombinant human Eli Lilly recombinant treatment of seven sepsis Phase II activated protein C Indianapolis, IN human (rhAPC) protein recombinant human Genetics Institute interleukin infectious diseases Phase I/II interleukin-12 Cambridge, MA (see also cancer) (rhIL-12) Wyeth-Ayerst Laboratories Philadelphia, PA Rotashield ™ Wyeth-Lederle continuous prevention of rotaviral application rotavirus vaccine, Vaccine & Pediatrics cell line gastroenteritis in infants submitted live, oral, Philadelphia, PA vaccine tetravalent rotavirus Virus Research Institute vaccine rotavirus in infants Phase II vaccine Cambridge, MA Savvy ™ Biosyn microbicide infectious disease Phase I C31G Philadelphia, PA Tenefuss ® Hoffmann-La Roche recombinant septic shock, severe sepsis Phase III Ienercept Nutley, NJ soluble (TNF-receptor) receptor fusion protein) tifacogin Chiron tissue factor sepsis Phase II Emeryville, CA pathway Searle inhibitor Skokie, IL INFERTILITY Anfide ™ Ares-Serono and hormone- female infertility Phase I gonadotropin Serono Laboratories releasing hormone-releasing Norwell, MA hormone hormone antagonist antagonist (GhRHA) Gonal-P ® Serono Laboratories recombinant male infertility Phase III recombinant human Norwell, MA fertility follicle-stimulating hormone hormone (r-FSH) LhADI ® Ares-Serono and recombinant female infertility-follicular support, Phase II/III recombinant Serono Laboratories fertility stimulation of follicular development human leutinizing Norwell, MA hormone hormome (r-hLH) Ovidrel ® Ares-Serono and recombinant female infertility Phase III recombinant Serono Laboratories gonadotropin (see also AIDS/HIV) human chorionic Norwell, MA gonadotropin (r-hCG) NEUROLOGIC DISORDERS Activase ™ Genentech t-PA acute ischemic stroke within Phase III alteplase, S. San Francisco, CA 3 to 5 hours of symptom onset recombinant AnerglX ® MS Anergen functional multiple sclerosis Phase I Redwood City, CA antigenics immuno- therapy Antigen Athena Neurosciences MAb multiple sclerosis flares Phase II natalizumab S. San Francisco, CA ATM027 T Cell Sciences MAb multiple sclerosis Phase I humanized MAb Needham, MA Avonex ® Biogen interferon secondary, progressive Phase III interferon beta-1a Cambridge, MA multiple sclerosis (see also cancer) Betaseron ® Berlex Laboratories interferon chronic progressive multiple sclerosis Phase III recombinant Wayne, NJ (see also cancer) interferon beta-1b Chiron Emeryville, CA brain-derived Amgen growth arryotrophic lateral sclerosis Phase I neurotrophic factor Thousand Oaks, CA factor (BDNF) Regeneron Pharmaceuticals Tarrytown, NY CPC-211 Cypros Pharmaceuticals cellular ischermic stroke, traumatic brain Phase II Carlsbad, CA therapy injury enlimomab Boehringer Ingelheim MAb stroke Phase II/III (anti-ICAM-1 MAb) Pharmaceuticals (see also other) Ridgefield, CT FIBLAST ® Scios growth stroke Phase II/III trafermin Mountain View, CA factor (see also heart) Wyeth-Ayerst Laboratories Philadelphia, PA Hu23F2G ICOS MAb multiple sclerosis, ischemic stroke Phase II MAb Bothell, WA (See also heart, other) interleukin-10 Schering-Plough interleukin multiple sclerosis Phase I (IL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, respiratory, skin) IR 208 Immune Response Corp. vaccine multiple sclerosis Phase I therapeutic vaccine Carlsbad, CA LDP-01 LeukoSite MAb stroke Phase I/II Cambridge, MA (see also transplantation) MS-TCR Connetics vaccine multiple sclerosis Phase I/II Palo Alto, CA Myotrophin ® Cephalon growth amyotrophic lateral sclerosis application rhIGF-1 West Chester, PA factor submitted Chiron peripheral neuropathies Phase II Emeryville, CA NeuroCell ™-FE Diacrin cellular focal epilepsy Phase I (cellular Charlestown, MA therapy transplantation therapy) NeuroCell ™-HD Diacrin cellular Huntington's disease Phase I (cellular Charlestown, MA therapy completed transplantation Genzyme Tissue Repair therapy) Cambridge, MA NeuroCell ™-PD Diacrin cellular Parkinson's disease Phase II (cellular Charlestown, MA therapy transplantation Genzyme Tissue Repair therapy) Cambridge, MA neutrophin-3 Amgen growth enteric neuropathics Phase I/II Thousand Oaks, CA factor Regeneron Pharmaceuticals Tarrytown, NY pimagedine Alteon overt neuropathy Phase III Ramsey, NJ (see also diabetes) Genentech S. San Francisco, CA prosaptide Myelos Neurosciences growth neuropathic pain and peripheral Phase II TX14(A) San Diego, CA factor neuropathy Rebii ® Serono Laboratories interferon relapsing, remitting multiple sclerosis; application recombinant Norwell, MA transitional multiple sclerosis submitted interferon beta-1a (see also cancer, infectious diseases) ReoPro ® Centocor MAb stroke Phase II abciximab Malvern, PA (see also heart) Eli Lilly Indianapolis, IN Spheramine ™ Titan Pharmaceuticals cellular Parkinson's disease Phase I S. San Francisco, CA therapy Zenapex ® Hoffmann-La Roche MAb tropical spastic paraparesis Phase I/II daclizumab Nutley, NJ (model for multiple sclerosis) Protein Design Labs (see also cancer, eye, skin, Mountain View, CA transplantation RESPIRATORY DISEASES AAV CFTR Targeted Genetics gene therapy sinusitis Phase I gene therapy Seattle, WA (see also genetic) acellular pertussis Chiron vaccine pediatric pertussis application vaccine Emeryville, CA (whooping cough) submitted anti-IgE Genentech MAb allergic asthma Phase III humanized MAb S. San Francisco, CA allergic rhinitis Phase II Novartis Pharmaceuticals East Hanover, NJ Tanox Biosystems Houston, TX Influenza rHAO Protein Sciences vaccine prevention of influenza Phase II Vaccine Meriden, CT influenza vaccine influenza virus Aviron vaccine prevention of influenza Phase III vaccine Mountain View, CA (live, attenuated) interleukin-4 Immunex recombinant asthma Phase I receptor Seattle, WA soluble receptor interleukin-10 Schering-Plough interleukin acute lung injury Phase I (IL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, neurologic, skin) Iisolylline Cell Therapeutics acute lung injury Phase II Seattle, WA (see also other) NEUPOGEN ® Amgen colony multilobar pneumonia, Phase III Filgrastim Thousand Oaks, CA stimulating pneumonia sepsis (rG-CSF) factor (see also AIDS/HIV, cancer) Oxsodrol ® bio-Technology General dismutase bronchopulmonary dysplasia Phase III rhCuZr super Iselin, NJ in premature infants dismutase parainfluenza Aviron vaccine prevention of parainfluenza type-3 Phase II type-3 vaccine Mountain View, CA infection (cause of croup in infants) (live, attentuated bovine) PIV vaccine, Wyeth-Lederle continuous prevention of parainfluenza Phase I live, attentuated Vaccines & Pediatrics cell line virus-mediated lower respiratory Philadelphia, PA vaccine disease in infants Quillerimmune-F Aquila Biopharmaceuticals vaccine pneumococcal infections in Phase II Worcester, MA the elderly recombinant ICOS acute respiratory distress syndrome, Phase II platelet activating Bothell, WA asthma factor- (see also digestive) acetylhydrolase (rPAF-AI-1) RSV subunit Wyeth-Lederle continuous prevention of respiratory syncytial Phase II vaccine Vaccines & Pediatric cell line virus-mediated lower respiratory Philadelphia, PA vaccine disease in the elderly and at-risk children RSV vaccine, Wyeth-Lederle continuous prevention of respiratory syncytial Phase I live, attenuated Vaccines & Pediatrics cell line virus-mediated lower respiratory Philadelphia, PA vaccine disease in infants soluble ICAM-1 Boehringer Ingelheim recombinant prevention and/or treatment of Phase II (BIRR4) Pharmaceuticals soluble rhinovirus-induced common cold Ridgefield, CT receptor Synagis ™ Mediummune MAb prevention of respiratory syncytial application MEDI-493 Gaithersburg, MD virus disease submitted humanized RSV MAb TP10 T Cell Sciences recombinant acute respiratory distress syndrome Phase II Needham, MA soluble (see also heart, transplantation) receptor truncated ICAM Bayer adhesion rhinovirus-associated Phase I Berkeley, CA molecule exacerbations of asthma SKIN DISORDERS anti-CD11a Genentech Mab moderate to severe psoriasis Phase II humanized MAb S. San Francisco, CA (hu1124) XOMA Berkeley, CA gamma interferon Connetics interferon iceloids Phase II Palo Alto, CA ICM3 ICOS Mab psoriasis Phase I Bothell, WA IL-2 fusion protein Seargen fusion moderate to severe psoriasis Phase I/II DAB₃₈₉IL-2 Hopkinton, MA protein (see also autoimmune, cancer) interleukin-10 Schering-Plough interleukin psoriasis Phase I (IL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, neurologic, respiratory) IR 502 Immune Response Corp. vaccine psoriasis Phase II therapeutic Carlsbad, CA vaccine ISIS 2302 Isis Pharmaceuticals antisense psoriasis Phase II Carlsbad, CA (see also autoimmune, digestive, transplantation) keratinocyte Human Genome Sciences growth wound healing Phase I growth factor-2 Rockville, MD factor (see also other) (KGF-2) LFA3TIP Biogen recombinant psoriasis Phase II Cambridge, MA T-cell inhibitor Regranex ™ Chiron growth pressure ulcers Phase III becaplernin Emeryville, CA factor (see also other) (recombinant R. W. Johnson human Pharmaceutical platelet-derived Research Institute growth factor-88) Raritan, NJ T4N5 Liposome Applied Genetics protection against actinic keratoses Phase III Lotion Freeport, NY in patients with xeroderma T4 endonuclease V pigmentosa encapsulated in liposomes TGF-beta3 OSI Pharmaceuticals growth impaired wound healing Phase II Uniondale, NY factor (see also other) transforming Novartis Pharmaceuticals growth wound healing Phase II growth East Hanover, NJ factor factor-beta-3 Zenapax ® Hoffmann-La Roche MAb psoriasis Phase I/II daclizumab Nutley, NJ (see also cancer, eye, neurologic, Protein Design Labs transplantation) Mountain View, CA TRANSPLANTATION allogeneic SyStemix cellular correct genetic diseases by in utero Phase I hematopoietic Palo Alto, CA therapy transplantation of genetically stem cells unaffected cells from a sibling or parent CBL antibody Abgenix Mab graft versus host disease Phase II (ABX-CBL) Foster City, CA CTLA41g Bristol-Myers Squibb recombinant immunosuppression PHase II Princeton, NJ soluble receptor HSD-Tk Genetic Therapy gene therapy treatment of graft versus host disease Phase I retroviral vector Gaithersburg, MD in allogeneic hematopoietic SyStemix stem cell transplantation Palo Alto, CA HSV-tk Chiron gene therapy graft versus host disease Phase I Emeryville, CA in bone marrow transplantation ISIS 2302 Isis Pharmaceuticals antisense renal transplant rejection Phase II Carlsbad, CA (see also autoimmune, digestive, skin) LDP-01 LeukoSite MAb kidney transplantation Phase I/II Cambridge, MA (see also neurologic) MEDI-507 Medimmune MAb graft versus host disease Phase II (humanized Gaithersburg, MD acute kidney transplant rejection Phase I/II MAb) BioTransplant Charlestown, MA ORTHOCLONE Ortho Biotech MAb prevention of organ transplant Phase II OKT4A Raritan, NJ rejection (see also autoimmune) Simulect Novartis Pharmaceuticals MAb transplantation application basiliximab East Hanover, NJ submitted SMART ™ Anti-CD3 Protein Design Labs MAb organ transplantation Phase I HuM291 Mountain View, CA (see also autoimmune) TP10 T Cell Sciences recombinant transplantation Phase I/II Needham, MA soluble (see also heart, respiratory) receptor Zenapax ® Hoffmann-La Roche MAb liver transplantation Phase II daclizumab Nutley, NJ (see also cancer, eye, neurologic, skin) Protein Design Labs pediatric kidney transplantation Phase I/II Mountain View, CA Zenapax ® Hoffmann-La Roche MAb kidney transplant rejection, Phase I/II daclizumab Nutley, NJ cyclosporine elimination and Protein Design Labs Cellcept ® Mountain View, CA OTHER Recomburmin Centeron excipient use Phase I recombinant King of Prussia, PA human albumin Regranex ™ Chrion growth venous ulcers Phase III becaplermin Emeryville, CA factor (see also skin) (recombinant R. W. Johnson human Pharmaceutical platelet-derived Research Institute growth factor-88) Raritan, NJ rhBMP-2 Genetics Institute growth bone and cartilage repair in clinical Cambridge, MA factor trials Saizen ® Serono Laboratories human chronic renal failure in children Phase III somatropin Norwell, MA growth (see also growth disorders) (rDNA origin) hormone post-operative recovery Phase II for injection Serostint ™ Serono Laboratories human metabolic conditions Phase II somatropin Norwell, MA growth (see also cancer) (rDNA origin) hormone for injection Somatokine ® Celtrix Pharmaceuticals growth hip fractures, severe acute burns Phase II recombinant Santa Clara, CA factor insulin-like growth factor-1/ binding protein-3 TGF-beta3 OSI Pharmaceuticals growth oral mucositis Phase II Uniondale, NY factor (see also skin) The content of this survey has been obtained through government and industry sources based on the latest information. Survey current as of Mar. 13, 1998. The information may not be comprehensive. For more specific information about a particular product, contact the individual company directly. PhRMA Internet address: http://www.phrma.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 1998 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

In one aspect, particular benefit is obtained with this invention when used with biopharmaceuticals, which include, for example, any proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids or other biopolymers. Specific examples of biopharmaceuticals to be included in the crystal formulations of the present invention include the following: insulin, glucagon, Glucagon-Like Peptide-1 (7-37)OH (GLP-1), human growth hormone, leptin, follicle-stimulating hormone (FSH), ribozyme, and analogs thereof.

The API's useful with the present invention include those which themselves may form crystalline products, as well as those which do not. By way of example, any proteins can be prepared as microcrystalline suspension products, but the results have frequently been unsatisfactory using existing technology. However, inclusion of these biomolecules into a host crystal system in accordance with the present invention overcomes this limitation on crystallization. The invention further finds utility even with API's that are readily crystallized, such as insulin. The incorporation of such API's into a single crystal lattice can be used to enhance stability or provide means of delivery that have different characteristics.

Solvents for preparation of the saturated and supersaturated crystal lattice component include, but are not limited to, water alcohols (e.g., ethanol, isoproponal), other organic solvents, acids, bases, and buffers.

The crystals of the present invention are prepared to have a predetermined amount of active pharmaceutical ingredient. The desired amount of active pharmaceutical ingredient will depend on typical considerations, such as the effective amount of API used for administering to a patient. The concentration of API in the crystal is controlled, such as by previously described means, to yield crystals which are readily used in preparing pharmaceutical formulations for administration. The active pharmaceutical ingredient can be incorporated into the crystals at any of a wide variety of molar or weight percentages. Preferred percentages can be easily selected by a skilled artisan taking into account the usual considerations for later formulation of the desired pharmaceutical compositions, depending on the application, route of delivery, and desired pharmacological profile. Preferred percentages include, for example, concentrations of 0:01–1 weight percent. As used herein, all weight percentages are given as the percent based on the weight of the crystal including the crystal lattice component, the active pharmaceutical ingredient and any other components included within the crystals, unless stated otherwise.

The crystals may be prepared at varying size distributions, similarly depending on the subsequent formulating to be done with the crystals, or on crystal growth parameters. The crystals may be harvested and then sorted directly to desired size ranges, or may first be processed, such as by grinding or milling, and then sorted such as by sieving. As will be appreciated, a desired amount of active pharmaceutical ingredient may be obtained simply by obtaining a determined weight of crystals containing the active pharmaceutical ingredient at a known weight concentration. The useful size or weight range of the crystals of the present invention accordingly varies widely, depending on such factors as the inclusion level of the active pharmaceutical ingredient, the dosage amount for the active pharmaceutical ingredient, and the method of delivery of the crystals. By way of example, suitable crystals may have an average size distribution of 1 μm to 1 mm.

The crystals of the present invention will typically be used in a formulation comprising a large number of crystals. It is a feature of the present invention that the active pharmaceutical ingredient is included within the crystal lattice component in a predictable, oriented fashion. This leads to a uniform concentration of the active pharmaceutical ingredient as a molar, and therefore weight, percentage of the crystals. In one aspect of the present invention, there is provided a composition of crystals having a substantially uniform weight concentration of active pharmaceutical ingredient as between crystals. The term “substantially uniform weight concentration” refers to the fact that the weight concentration of active pharmaceutical ingredient in the various crystals is sufficiently uniform that an acceptably accurate weight of active pharmaceutical ingredient can be obtained based on the weight of the crystals and the average concentration of active pharmaceutical ingredient in such crystals. In one preferred embodiment, there is provided a composition of crystals in which the size distribution of active pharmaceutical ingredient does not vary between crystals by more than about 20 percent. However, alternate embodiments may be equally useful, including mixtures of different size crystals. A desired quantity of active pharmaceutical ingredient is then accurately obtained by measuring a weight amount of crystals which, given the concentration of active pharmaceutical ingredient, yields the selected weight of active pharmaceutical ingredient.

The crystals and included API's are useful in the crystal form for both the stabilization and storage of the API and for the administration of the API to a patient. As used herein, it will be appreciated that the term patient refers to either humans or non-humans, depending on the nature of the active pharmaceutical ingredient. The crystals may be used as such, and in one aspect of the present invention the crystals consist essentially of simply the crystal lattice component and the API. Alternatively, the crystals include the crystal lattice component and the API in combination with other pharmaceutically-acceptable adjuvants also contained within the crystals.

The crystals of the present invention are preferably formulated as pharmaceutical materials for ultimate delivery in solid or liquid form. In such applications, the crystals are typically formulated with common, compatible, pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. For purposes herein, the term “pharmaceutically-acceptable” refers in this context to the excipients, diluents or carriers, as well as coatings or other components referred to elsewhere, being compatible with the other ingredients of the formulation and no deleterious to the recipient thereof.

Examples of excipients, diluents, and carriers that are suitable for such dosage forms are well known in the art, and include the following: suspension additives such as tonicity modifiers, buffers, precipitants, and preservatives; fillers and extenders such as starch, lactose, dextrose, sucrose, sorbitol, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. Additionally, the adjuvant may comprise crystals of the crystal lattice component that are prepared without the included API.

The crystals may be coated to achieve various effects. In one approach, the crystals are coated with the same crystal lattice component which forms the underlying crystal, but without the include API. This assures that the coating and the underlying crystal have compatibility. The coating is then applied at a thickness which provides the desired effect, such as further protection of the active pharmaceutical ingredient, bulking of the crystal for handling, and/or effecting a sustained or delayed release of the active pharmaceutical ingredient. Alternatively, the same effects can be accomplished by coating the crystals with other compatible coating compositions, such as those which are well known in the pharmaceutical coating art. The crystals can also be coated so as to release the active pharmaceutical ingredient only or preferably in a particular part of the intestinal tract or other route of administration, possibly over a period of time. This is accomplished, in known fashion, using coatings, envelopes, and protective matrices made, for example, from polymeric substances or waxes.

it is a feature of one aspect of the present invention that the crystals and included API's may be packaged and administered to patients in discrete pharmaceutical dosage forms. The crystals may be used as such in solid form, or may be formulated into liquid solutions or suspensions prior to use. The compositions may accordingly be administered by various routes, for example, by the oral, rectal, vaginal, ocular, buccal, nasal, pulmonary, iontophoretic, topical or parenteral routes. Such compositions form part of the present invention and are prepared in manners well known in the pharmaceutical art.

The API's of the present invention are effective over a varied dosage range. Such dosages are readily accommodated by the present invention by permitting various sizes of crystals, concentrations of API, etc. It will be understood that the amount administered will be determined in light of the relevant circumstances, including the condition to be treated, the choice of API to be administered, the size of the patient being treated, and the chosen route of administration. Therefore, specific dosage ranges will differ accordingly, and are not limiting of the scope of the invention in any way.

The compositions are formulated in one embodiment as a unit dosage form. The term “unit dosage form” refers to physically discrete units, such as tablets, capsules, and suspensions in vials or cartridge/pen systems suitable as unitary dosages, particularly as unitary daily dosages. Each discrete unit contains a predetermined quantity of active pharmaceutical material calculated to produce the desired effect, e.g., a prophylactic or therapeutic effect. The amount of active pharmaceutical ingredient contained in a given dosage unit can be varied depending on the manner of delivering the crystals. For example, a single dosage unit in tablet form may contain ¼, ⅓, ½ or 1 times the unit dose for the active pharmaceutical ingredient, according to which 1 to 4 tablets would be administered to achieve a unit does of the active pharmaceutical ingredient.

Therefore, in one aspect of the present invention, there is provided a pharmaceutical product in dosage form comprising a pharmaceutical delivery unit including a dosage amount of active pharmaceutical ingredient. The API is contained within the crystal lattice component, and a sufficient amount of crystals is included within the delivery unit to constitute the dosage amount of the API. It will be appreciated that the dosage amount of pharmaceutical may be obtained by provision of one or more crystals of the present invention. One form of the product consists essentially of a dosage amount of the crystals. In an alternative form, the pharmaceutical product consists of the dosage amount of the crystals.

The ultimate delivery forms may include, for example, tablets, soft and hard gelatin capsules, pellets, granules, marumes, lozenges, sachets, cachets, elixirs, suspensions, ointments, suppositories, injection solutions and suspensions, nonpareils, spheres and sterile packaged powders. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants, including excipients, diluents and carriers, as already described. One preferred form of the pharmaceutical product consists essentially of the crystals, and an alternate form consists of the crystals and the pharmaceutically-acceptable adjuvants. The delivery forms are prepared by conventional techniques such as disclosed in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, Pa. (1995), which is incorporated herein by reference, or other treatises available to the skilled artisan.

Compressed tablets, for example, are prepared by well-known means which are conventional in the art. The tablets may be prepared by wet or dry granulation methods or by direct compression, and may be produced by any of a wide variety of tabletting machines. Tablet formulations usually incorporate diluents, binders, lubricating and disintegrators, as well as the crystals with included API's. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

Certain solid pharmaceutical dosage forms of the present invention, most notably tablets, may be coated in conventional fashion with a wide variety of materials utilizing various processes. Typically, the products of the present invention may be sugar coated or film coated in accordance with well-known techniques. The coatings serve as aesthetic purpose as well as a pratical one. Coatings can mask an unpleasant taste or odor, can increase ease of ingestion by the patient, and can serve to improve the ultimate appearance of the dosage form. Similarly, coatings can protect the product from the effects of air, moisture and light, can improve product identification, and can facilitate handling in packaging and fill lines during manufacture.

Various adjuvants may be included in the coating formulations as is well known in the art. These include, for example, permeability enhancers, plasticizers, antitacking agents and the like. A discussion of coating techniques and adjuvants is presented in U.S. Pat. No. 5,015,480, issued to Childers et al. on May 14, 1991, the pertinent portions of which are hereby incorporated herein by reference. Further information pertinent to coating processes and equipment may be obtained from Remington's Pharmaceutical Sciences, supra.

Tables are often coated with sugar as a flavorant and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the subject consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some subjects.

A lubricant is used in a tablet formulation to prevent the tablet and punches from sticking in the die of the tabletting machine. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break up the tablet and release the crystals. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.

Enteric formulations are used to protect crystals and the included API's from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

The crystals with included API's may similarly be formulated into capsules for administration. Such capsules are prepared utilizing conventional encapsulating methods. A general method of manufacture involves preparing the crystals for use in capsules, such as by milling the crystals to a suitable size. The crystals are blended with desired excipients, diluents or carriers, and the resulting mixture is filled into suitably-sized capsules, typically hard gelatin capsules, using conventional capsule-filling machines. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powers.

When it is desired to administer the crystal formulations as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are also in wide use.

The crystals can also be similarly formulated as elixirs or suspensions for convenient oral administration or for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.

The inventive crystals enable the design of sustained-release formulations based upon various factors to yield both the desired amount of active pharmaceutical ingredient and the desired pharmacokinetic profile for delivery of the active pharmaceutical ingredient. Selectively incorporating the active pharmaceutical ingredient into the crystal lattice, e.g., into a specific crystal growth sector, modulates the release profiles and can therefore be used to effect desired pharmacological properties. The choice of the crystal component and the process used to grow the crystals of excipient host and guest active pharmaceutical ingredient can be selected and/or modified to adjust parameters such as the delivery rate of the active pharmaceutical ingredient upon use of the formulation. The active pharmaceutical ingredient is incorporated into the crystal matrix at a selected rate, typically as only a small weight percentage of the overall crystal. The permits moderate and uniform rates of release.

Various approaches may be used to accomplish a delayed or sustained release of active pharmaceutical ingredient from the crystals. In a typical application the crystal of the desired size are combined with a compatible preservative and the mixture is injected subcutaneously or surgically implanted to provide a prolonged payout as the crystals dissolve as a result of contact with the surrounding body tissue and fluid. In one approach, the concentration of the active pharmaceutical ingredient in the crystals is reduced in order to effect a sustained release over time. Alternatively, larger crystals may be used to provide for more prolonged payout of the active pharmaceutical ingredient. In another approach, coatings on the crystals are used to affect the rate of release of the active pharmaceutical ingredient. Such coatings may comprise the same crystal lattice component but without the included active pharmaceutical ingredient, as well as other coating compositions useful for this purpose.

In the alternative, the crystals of the present invention can be used to isolate and/or store the active pharmaceutical ingredient for later reconstitution into solution. The crystals may be stored for extended periods of time prior to reconstitution in view of the added stability accorded the API's by the encompassing crystal lattice component. The crystals are then combined with pharmaceutically-acceptable excipients, diluents or carriers to prepare the solutions for subsequent administration. The crystals are readily dissolved or suspended in appropriate diluents, which may be selected, for example, from the list previously provided with regard to diluents used to initially prepare the crystals.

Such solutions of dissolved crystals provide the active pharmaceutical ingredient free of the previously encompassing crystal lattice component. The solutions are useful, for example, for oral administration, parenteral use, or as suppositories. For parenteral administration, for example, the crystals may be formulated in a pharmaceutically-acceptable diluent such as physiological saline (0.9%), 5% dextrose, Ringer's solution, and the like, along with other additives to reduce the solubility of the crystals in suspension.

The resulting pharmaceutical formulations provide an active pharmaceutical ingredient which is included within the host crystal and has enhanced stability and shelf-life. The present invention therefore satisfies the desire to provide certain pharmaceuticals having an acceptable, room-temperature shelf-life. Depending on the circumstances, particularly the API involved, the desired shelf-life can be as little as one month, or may be at least one year, two years or more. The pharmaceutical molecules are generally isolated from one another and from the environment by the surrounding crystal lattice. The containment of the API in the solid crystal lattice also fixes the conformational orientation. This eliminates most of the potential degradation mechanisms, such as polymerization, oxidation, deamidation and proteolysis, that could otherwise reduce the stability of the pharmaceutical.

Methods demonstrating stability include but are not limited to high-performance liquid chromatography for purity and potency, FT-IR for secondary structure, in-vitro and in-vivo bioassays, and pharmacokinetic profiles.

The crystals of the present invention are readily prepared and are useful in containing the included API in an isolated, oriented position within the lattice. The utility of the present invention is demonstrated in the following examples, which are illustrative in nature, and are not to be considered limiting of the scope of the present invention.

EXAMPLE 1

To demonstrate the potential kinetic stabilization of proteins, green fluorescent protein (GFP) was incorporated into deionized α-lactose monohydrate. GFP was selected because it is known to fluoresce only in its native conformation. Upon denaturation, the interior of the β-barrel of the molecule is exposed and the fluorescence of the p-hydroxybenzylideneimidazolinone chromophore is rapidly quenched. Typical crystal growth conditions involved the addition of 8 volumes of an approximately 1 mg/mL (approximately 37 μmole) solution of GFP in 10 mM tris-HCl, pH8 and 10 mM EDTA to 100 volumes of a supersaturated aqueous solution (approximately 1.15 M) of deionized α-lactose monohydrate. The mixed solution was allowed to stand for 3–4 days at room temperature in a 24-well plate. Crystals were harvested between 1–3 days and displayed a hatchet morphology as shown in FIG. 1 with a broad base (010) further bounded by {100}, {110}, {1–10}, and {0–11}. Small (0–10) and {1–50} faces are also occasionally present. When illuminated with a long wavelength UV lamp, the crystals exhibited a bright green fluorescence localized within a sharply defined pyramid corresponding to the (010) growth sector. This indicates that GFP is selectively recognized and overgrown by the (010) face in preference to the others. More importantly, it is evidence that the GFP is in its native conformation. The level of GFP to lactose is approximately 0.008% (w/w).

GFP fluorescence intensity was measured as a function of time and temperature in three environments: saturated aqueous α-lactose solution, lyophilized α-lactose, and crystalline α-lactose monohydrate. As shown in FIG. 2, both the solution and lyophilized preparations lost nearly half of the fluorescence intensity at 333° K. within one hour. The crystal showed no change at 333° K. or even 343° K.

EXAMPLE 2

To investigate the potential for incorporation of a biopharmaceutical into crystals of biocompatible excipients, studies were conducted using rhodamine-labeled glandular glucagon and lactose. As in the previous studies, the rhodamine label was used to facilitate the visualization of glucagon in the host crystals. Typical crystal growth conditions involved the addition of 5 volumes of a supersaturated solution of deionized α-lactose monohydrate to 1 volume of an approximately 1.5 mg/mL (approximately 300 to 400 μmole) of rhodamine-labeled glucagon in purified water. The mixed solution was allowed to stand at room temperature in a 24-well plate. Crystals were harvested between 1–3 days and displayed a hatchet morphology with a broad base. With the rhodamine label, glucagon inclusion was visible in the crystals as a well-defined pyramid corresponding to the (010) growth sector. The level of inclusion was determined to be approximately 0.1% (w/w).

In-vitro dissolution experiments were performed on the glucagon/lactose crystals to evaluate potential for in-vivo, sustained-release pharmacokinetics. The release of rhodamine-labeled glucagon into solution was followed by fluorescence spectroscopy. In a typical experiment, 1–2 crystals were added to 100 microliters of phosphate buffered saline solution at room temperature and the increase in fluorescence of the solution was monitored over time. The release of glucagon from the dissolving crystals was generally complete after 24–48 hours depending on crystal size and was linear until the last few hours of dissolution. Additional details are contained in the article entitled “Stabilization of Proteins in Single Crystal Hosts: Green Fluorescent Protein and α-Lactose Monohydrate,” M. Kurimoto, P. Subramony, R. Gurney, S. Lovell, J. A. Chmielewski, B. Kahr, J. Am. Chem. Soc. 1999, 121, 6952–6953, which article is hereby incorporated herein by reference.

EXAMPLE 3

To demonstrate the universality of this technology for incorporation of a diversity of biopharmaceuticals into crystals of biocompatible excipients, studies were conducted using biosynthetic human insulin and insulin analogs, V8-GLP-1(7–37)OH, a glucagon-like insulinotropic peptide-1 analog, exendin, and human growth hormone in deionized α-lactose monohydrate or phthalic acid. Information regarding V8-GLP is available in U.S. Pat. No. 5,705,483, issued to Galloway and Hoffman on Jan. 6, 1998, which patent is hereby incorporated herein in its entirety. For information regarding exendin, see, e.g., R. Goke, H. C. Fehmann, T. Linn, H. Schmidt, M. Krause, J. Eng, B. Goke, “Exendin-4 is a High Potency Agonist and Truncated Exendin-(9-39)-amide an Antagonist at the Glucagon-like Peptide 1-(7-36)-amide Receptor of Insulin-secreting Beta-cells,” J. Biol. Chem. 1993, Sep 15, 268(26), pp. 19650-5, which reference is hereby incorporated herein in its entirety.

Typical crystal growth conditions involved the addition of 1 volume of an approximately 10 mg/mL rhodamine- or Texas red-labeled peptide or protein in 0.1M phosphate-buffered saline solution (PBS, pH7.4) to 10 volumes of a supersaturated α-lactose solution or phthalic acid solution. Supersaturated solutions of purified α-lactose were obtained by adding 0.41 grams of α-lactose to 1 mL of purified water, allowing to dissolve in a 50–70° C. water bath, and cooling to room temperature. Supersaturated solutions of phthalic acid were prepared by adding 0.05 grams of phthalic acid to 1 mL of either 70/30 (v/v) water/acetonitrile or 90/10 water/ethanol, allowing to dissolve in a 50–70° C. water bath, and cooling to room temperature. Larger volumes of supersaturated solutions are obtained by using the same solute-to-solvent ratio.

The solutions of labeled peptide or protein with the supersaturated α-lactose or phthalic acid were mixed by swirling, transferred to a 24-well crystallization plate or other suitable glass or polypropylene container, and allowed to stand at room temperature. Crystals were harvested in 4–5 days and rinsed with hexanes, ethanol, or methanol. All preparations yielded crystals with dye-labeled protein inclusions as determined by microscopic examination using an Olympus SZ-40 microscope with a CCD vision camera.

The shape of the crystals formed was dependent on the solvent system used for the phthalic acid. The crystals formed with phthalic acid in water/ethanol were long, petal-shaped clusters. The crystals formed with water/ethanol were smaller and rhombic. Crystals of labeled-insulin/lactose were dissolved in PBS and analyzed by HPLC. The level of insulin inclusion was determined to be approximately 0.1%. This process is scalable from 100 μL to several liters. The larger volume crystallizations were performed using glass beakers, or other appropriate large containers, covered with watch glasses.

Using the same process, unlabeled insulin and exendin have also been incorporated into α-lactose monohydrate and phthalic acid crystals. Upon dissolution of the crystals with 0.01N HCl, purified water and/or methanol, the level of peptide included in these hosts was determined by analysis of the sample solutions with an HPLC system in the flow-injection analysis mode using a chemiluminescent nitrogen-specific detector (CLND). The level of peptide inclusions ranged from approximately 0.1% to 10% (w/w). These data demonstrate that the level of inclusion can be manipulated by appropriate choice of guest and host molecules in addition to crystallization conditions. See also the following reference which are hereby incorporated herein in their entirety: M. Windholz, (editor). Merck Index, 10^(th) edition, p. 769; R. A. Visser, Neth. Milk Dairy Journal, 34, 1980, pp. 255–275; J. Chmielewski, et al., JACS, 119, 43, pp. 105665–10566. 

1. A pharmaceutical composition comprising: a single crystal of a pharmaceutically-acceptable crystal lattice component; and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure; wherein said crystal lattice component consists essentially of lactose.
 2. The invention of claim 1 and further comprising a pharmaceutically-acceptable adjuvant selected from the group consisting of excipients, diluents, carriers and mixtures thereof.
 3. The invention of claim 1 in which the active pharmaceutical ingredient is a biopharmaceutical.
 4. A pharmaceutical material comprising: a mixing of single crystals, each crystal comprising a pharmaceutically-acceptable crystal lattice component and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure; wherein said crystal lattice component consists essentially of lactose.
 5. The pharmaceutical material of claim 4 in which the crystals comprise at least two crystal lattice components, the first crystal lattice component being characterized by first pharmacokinetics and the second crystal lattice component being characterized by second pharmacokinetics.
 6. The pharmaceutical material of claim 4 in which said mixture comprises a mixture of two different types of said crystals, the first type of the crystal comprising a first crystal lattice component and the second type of the crystals comprising at least one crystal lattice component different from the first crystal lattice component.
 7. The pharmaceutical material of claim 4 in which the active pharmaceutical ingredient comprises discrete units and the units are included within the crystals in isolation from one another.
 8. The pharmaceutical material of claim 4 in which the active pharmaceutical ingredient is included within the crystal at a concentration of about 0.001 to 1 weight percent based on the weight of the crystal including the active pharmaceutical ingredient. 